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168 results on '"Pathologie vasculaire et endocrinologie rénale"'

1. REMY: the hypertrophic cardiomyopathy registry of the french society of cardiology

Author

Mirabel, M., Reant, P., Donnal, E., Suty-Selton, C., Huttin, O., Labombarda, F., Charron, P., Habib, G., Jeunemaître, X., Offredo, L., Tafflet, M., Jouven, X., Desnos, M., Hagege, A. A., Grp, Remy Study, Gestion de l'Eau, Acteurs, Usages ( UMR G-EAU ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -AgroParisTech-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture ( IRSTEA ) -Centre International des Hautes Études Agronomiques Méditerranéennes ( CIHEAM ) -Institut national d’études supérieures agronomiques de Montpellier ( Montpellier SupAgro ), Centre de résonance magnétique biologique et médicale ( CRMBM ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques de l'Hopital Europeen Georges Pompidou, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Collège de France ( CDF ), Collège de France ( CdF ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Gestion de l'Eau, Acteurs, Usages (UMR G-EAU), Institut de Recherche pour le Développement (IRD)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-AgroParisTech-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CDF), Collège de France (CdF), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-AgroParisTech-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CdF (institution)), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), and COMBE, Isabelle

Subjects
[ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Abstract

Congress of the European-Society-of-Cardiology (ESC), Rome, ITALY, AUG 27-31, 2016; International audience; no abstract

Published
2016

2. Interaction of the coiled‐coil domain with glycosaminoglycans protects angiopoietin‐like 4 from proteolysis and regulates its antiangiogenic activity

Author

Sylvie Ricard-Blum, Clément Faye, Corinne Ardidie-Robouant, Clémence Chomel, Laurent Muller, Stéphane Germain, Aurélie Cazes, A. Barret, Catherine Monnot, Elisa Gomez, Marine Bignon, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Vascular Genomics Network (http://www.evgn.org) (contract LSHMCT-2003-503254), ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease(2006), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Experimental Medicine Unit, Collège de France ( CdF ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie A [CHU HEGP], and ANR-06-JCJC-0160,ANGPTL4,Role of ANGPTL4 during development and ischemic heart disease ( 2006 )

Subjects
MESH : Cell Line, MESH : Angiopoietins, Protein Conformation, Angiogenesis, MESH: Cricetinae, Biochemistry, Extracellular matrix, angiogenesis, MESH: Protein Structure, Tertiary, MESH: Protein Conformation, 0302 clinical medicine, MESH : Lipid Metabolism, Cricetinae, MESH: Animals, MESH : Protein Conformation, Glycosaminoglycans, MESH: Lipid Metabolism, 0303 health sciences, MESH : Neovascularization, Physiologic, medicine.diagnostic_test, Chemistry, MESH : Cricetinae, MESH : Extracellular Matrix, MESH : Protein Binding, MESH: Glycosaminoglycans, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cell biology, Endothelial stem cell, 030220 oncology & carcinogenesis, endothelial cell, MESH : Mutation, MESH : Protein Structure, Tertiary, MESH: Neovascularization, Physiologic, Protein Binding, Biotechnology, MESH: Mutation, extracellular matrix, Proteolysis, Neovascularization, Physiologic, Angiopoietin-like 4 Protein, MESH: Extracellular Matrix, Cell Line, Angiopoietin, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Glycosaminoglycans, Genetics, medicine, Animals, Humans, MESH: Protein Binding, Molecular Biology, 030304 developmental biology, MESH: Humans, hypoxia, MESH : Humans, Lipid Metabolism, Protein Structure, Tertiary, MESH: Cell Line, Cell culture, MESH: Angiopoietins, Mutation, MESH : Animals, Proprotein Convertases, Angiopoietins
Abstract

International audience; Angiopoietin-like 4 (ANGPTL4) is involved in angiogenesis and lipid metabolism. It is secreted by liver and adipose tissues and cleaved to generate circulating coiled-coil domain (CCD) and fibrinogen-like domain (FLD) fragments. The full-length ANGPTL4 produced by hypoxic endothelial cells interacts with the extracellular matrix (ECM). The ECM-bound and soluble forms of ANGPTL4 have antiangiogenic properties. We carried out a structure-function analysis to investigate the regulation of ANGPTL4 bioactivity in endothelial cells. We found that the recombinant CCD binds to the ECM, whereas the FLD is released into the medium. The CCD, like the full-length ANGPTL4, binds to heparan and dermatan sulfates in surface plasmon resonance assays and inhibits endothelial cell adhesion, motility, and tubule-like formation. In endothelial cells, ANGPTL4 is processed in the secretion medium after release from the ECM. This processing is altered by the proprotein convertases inhibitor alpha1-PDX and abolished by the mutation of the (161)RRKR(164) cleavage site without modification of the ECM binding and release. These data suggest that the full-length form, which interacts with heparan sulfate proteoglycans via its CCD, is protected from proteolysis by proprotein convertases and constitutes the major active pool of ANGPTL4 in hypoxic endothelial cells.

Published
2008
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3. Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Like2 regulate endothelial ECM and angiogenesis through non-catalytic scaffolding mechanisms

Author

Marion Marchand, Jérémie Teillon, Stéphane Germain, Claudia Umana-Diaz, Florence Ruggiero, Corinne Ardidie-Robouant, Marilyne Malbouyres, Christophe Guilluy, A. Barret, Catherine Monnot, Laurent Muller, Romain Salza, Sylvie Ricard-Blum, Yoann Atlas, Cathy Pichol-Thievend, Philippe Girard, Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assemblages Supramoléculaires Péricellulaires et Extracellulaires (ASPE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Inflammasome NLRP3 – NLRP3 Inflammasome, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), Institut Mutualiste de Montsouris (IMM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Collagen Type IV, 0301 basic medicine, Angiogenesis, [SDV]Life Sciences [q-bio], Neovascularization, Physiologic, Lysyl oxidase, Cell Line, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Human Umbilical Vein Endothelial Cells, medicine, Animals, Humans, Scavenger receptor, Molecular Biology, Zebrafish, Basement membrane, Binding Sites, LOXL2, biology, Chemistry, Dermis, Fibroblasts, Zebrafish Proteins, Extracellular Matrix, Fibronectins, Cell biology, Fibronectin, Surface coating, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutagenesis, Site-Directed, biology.protein, Amino Acid Oxidoreductases
Abstract

International audience; Lysyl oxidases are major actors of microenvironment and extracellular matrix (ECM) remodeling. These cross-linking enzymes are thus involved in many aspects of physiopathology, including tumor progression, fibrosis and cardiovascular diseases. We have already shown that Lysyl Oxidase-Like 2 (LOXL2) regulates collagen IV deposition by endothelial cells and angiogenesis. We here provide evidence that LOXL2 also affects deposition of other ECM components, including fibronectin, thus altering structural and mechanical properties of the matrix generated by endothelial cells. LOXL2 interacts intracellularly and directly with collagen IV and fibronectin before incorporation into ECM fibrillar structures upon exocytosis, as demonstrated by TIRF time-lapse microscopy. Furthermore, surface plasmon resonance experiments using recombinant scavenger receptor cysteine-rich (SRCR) domains truncated for the catalytic domain demonstrated their direct binding to collagen IV. We thus used directed mutagenesis to investigate the role of LOXL2 catalytic domain. Neither enzyme activity nor catalytic domain were necessary for collagen IV deposition and angiogenesis, whereas the SRCR domains were effective for these processes. Finally, surface coating with recombinant SRCR domains restored deposition of collagen IV by LOXL2-depleted cells. We thus propose that LOXL2 SRCR domains orchestrate scaffolding of the vascular basement membrane and angiogenesis through interactions with collagen IV and fibronectin, independently of the enzymatic crosslinking activity.

Published
2023
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4. Loss-of-function point mutations associated with renal tubular dysgenesis provide insights about renin function and cellular trafficking

Author

Laurent Muller, Jean-Marie Gasc, Maud Clemessy, Daniel Bur, Marie-Claire Gubler, Olivier Gribouval, Xavier Iturrioz, Pierre Corvol, Annie Michaud, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paul Verlaine - Metz (UPVM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Angiogénèse embryonnaire et pathologique, Iturrioz, Xavier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Mutant, medicine.disease_cause, Kidney Tubules, Proximal, 0302 clinical medicine, Pregnancy, Cricetinae, Gene duplication, [CHIM] Chemical Sciences, Renin, Missense mutation, Genetics (clinical), Cellular localization, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Mutation, General Medicine, Recombinant Proteins, 3. Good health, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV] Life Sciences [q-bio], Protein Transport, Female, medicine.medical_specialty, Molecular Sequence Data, CHO Cells, Biology, Cell Line, 03 medical and health sciences, Cricetulus, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Renin–angiotensin system, Genetics, medicine, [CHIM]Chemical Sciences, Animals, Humans, Point Mutation, Amino Acid Sequence, Molecular Biology, Loss function, 030304 developmental biology, Point mutation, Protein Structure, Tertiary, Endocrinology, Urogenital Abnormalities, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

Renal tubular dysgenesis (RTD) is a recessive autosomal disease characterized by persistent fetal anuria and perinatal death. During the systematic screening of mutations of the different genes of the renin-angiotensin system associated with RTD, two missense mutations in the renin gene were previously identified, the first affects one of the two catalytic aspartates (D38N) of renin, and the second, S69Y, is located upstream of the 'flap', a mobile β-hairpin structure which covers the substrate-binding site of renin. Here we report a novel renin mutation leading to the duplication of the tyrosine residue Y15dup, homologous to Y9 in some other aspartyl proteases, which seems to play a crucial role along the activation pathway. The biochemical and cellular mechanisms underlying renin inactivation were investigated. We expressed prorenin constructs harboring the identified point mutations in two established cell lines, able (AtT-20 cells) or unable (CHO cells) to process prorenin to renin and we evaluated the cellular localization of renin mutants and their functional properties. All three mutants were misfolded to different levels, were enzymatically inactive and exhibited abnormal intracellular trafficking. We suggest a misfolding of Y15dup renin, a partial misfolding of D38N prorenin and a misfolding of S69Y prorenin leading to complete absence of secretion. The structural consequences of the renin mutations were estimated by molecular modeling, which suggested some important structural alterations. This is the first characterization of the mechanisms underlying loss of renin function in RTD.

Published
2010
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5. Hybridisation of constraint solving with an ant colony algorithm for vehicle on-line path planning

Author

Guettier, C., Lucas, F., Siarry, P., Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), SIMO, Laboratoire Images, Signaux et Systèmes Intelligents (LISSI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Amirat, Yacine, Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Images, Signaux et Systèmes Intelligents ( LISSI ), and Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )

Subjects
[ MATH.MATH-OC ] Mathematics [math]/Optimization and Control [math.OC], [MATH.MATH-OC] Mathematics [math]/Optimization and Control [math.OC], [MATH.MATH-OC]Mathematics [math]/Optimization and Control [math.OC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2009

6. Characterization of the first angiotensin-converting like enzyme in bacteria: Ancestor ACE is already active

Author

Guillaume Riviere, Jean-Pierre Bohin, K. Ravi Acharya, Edward D. Sturrock, Didier Vieau, Pierre Corvol, Hazel R. Corradi, Annie Michaud, Virginie Cogez, Unité Neurosciences et Physiologie Adaptative, Université de Lille, Sciences et Technologies, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biology and Biochemistry, University of Bath [Bath], Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mca, 7-methoxycoumarin-4-yl)-diacetyl, Protein Conformation, DNase, desoxyribonuclease, Angiotensin-Converting Enzyme Inhibitors, Biochemistry, FPLC, fast protein liquid chromatography, bp, base pair(s), ACE, gene encoding ACE, Cloning, Molecular, Peptide sequence, Phylogeny, DpaOH, N3(2,4-dinitrophenyl)l-2,3-diaminopropionyl-OH, HHL, Hippuryl-Histidyl-Leucine, chemistry.chemical_classification, 0303 health sciences, cDNA, DNA complementary to RNA, biology, Angiotensin II, 030302 biochemistry & molecular biology, pv, pathovar RNase: ribonuclease, General Medicine, enk-NH2, enkephalinamide, enk, enkephalin, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Xanthomonas axonopodis, kDa, kilodalton, DMSO, dimethylsulfoxide, SDS, sodium dodecyl sulfate, rXcACE, recombinant Xanthomonas axonopodis pv citri Angiotensin-converting enzyme, Evolution, In silico, Molecular Sequence Data, Conservation, Peptidyl-Dipeptidase A, Article, CHO, chinese hamster ovary, kb, kilobase(s), Structure-Activity Relationship, 03 medical and health sciences, ORF, open reading frame, Xc, Xanthomonas axonopodis pathovar citri, Bacterial Proteins, Complementary DNA, Genetics, Amino Acid Sequence, C-, carboxy, ng, nanogram(s), PAGE, polyacrylamide gel electrophoresis, Ac, acetyl, 030304 developmental biology, Sequence Homology, Amino Acid, Structure, Computational Biology, Active site, ACE, Angiotensin-converting enzyme, dNTP, deoxyribonucleoside triphosphate, Carboxypeptidase, Protease, Open reading frame, Enzyme, nXcACE, native Xanthomonas axonopodis pv citri Angiotensin-converting enzyme, chemistry, HPLC, high-performance liquid chromatography, biology.protein, N-, amino, Angiotensin I, Genome, Bacterial, Ang, Angiotensin, Cloning
Abstract

International audience; Angiotensin-converting enzyme (ACE) is a metallopeptidase that converts angiotensin I into angiotensin II. ACE is crucial in the control of cardiovascular and renal homeostasis and fertility in mammals. In vertebrates, both transmembrane and soluble ACE, containing one or two active sites, have been characterized. So far, only soluble, single domain ACEs from invertebrates have been cloned, and these have been implicated in reproduction in insects. Furthermore, an ACE-related carboxypeptidase was recently characterized in Leishmania, a unicellular eukaryote, suggesting the existence of ACE in more distant organisms. Interestingly, in silico databank analysis revealed that bacterial DNA sequences could encode putative ACE-like proteins, strikingly similar to vertebrates' enzymes. To gain more insight into the bacterial enzymes, we cloned the putative ACE from the phytopathogenic bacterium, Xanthomonas axonopodis pv. citri, named XcACE. The 2 kb open reading frame encodes a 672-amino-acid soluble protein containing a single active site. In vitro expression and biochemical characterization revealed that XcACE is a functional 72 kDa dipeptidyl-carboxypeptidase. As in mammals, this metalloprotease hydrolyses angiotensin I into angiotensin II. XcACE is sensitive to ACE inhibitors and chloride ions concentration. Variations in the active site residues, highlighted by structural modelling, can account for the different substrate selectivity and inhibition profile compared to human ACE. XcACE characterization demonstrates that ACE is an ancestral enzyme, provoking questions about its appearance and structure/activity specialisation during the course of evolution.

Published
2007
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7. Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

Author

Stéphane Germain, Emmanuelle Le Coz, Lluis M. Mir, Josette Philippe, H. Mekid, Ariane Galaup, Elisabeth Connault, Catherine Monnot, Aurélie Cazes, Pierre Corvol, Paule Opolon, Sébastien Le Jan, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Germain, Stéphane, Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Vectorologie et transfert de gènes ( VTG / UMR8121 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
MESH : Mice, I, Lung Neoplasms, MESH: Lymphatic Metastasis, Melanoma, Experimental, Vascular permeability, MESH: Lymph Nodes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Metastasis, Carcinoma, Lewis Lung, Mice, 0302 clinical medicine, Cell Movement, MESH : Cell Movement, MESH : Female, MESH: Animals, Neoplasm Metastasis, MESH: Cell Movement, MESH : Lymph Nodes, 0303 health sciences, MESH : Melanoma, Experimental, Multidisciplinary, MESH: Carcinoma, Lewis Lung, biology, Lymphopoiesis, MESH : Lymphatic Metastasis, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biological Sciences, Vinculin, MESH: Lymphopoiesis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Melanoma, Experimental, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Female, Stress fiber, MESH: Cell Line, Tumor, MESH : Lymphopoiesis, Neovascularization, Physiologic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Angiopoietin-like 4 Protein, Capillary Permeability, Angiopoietin, MESH: Mice, I, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Carcinoma, Lewis Lung, Cell Line, Tumor, MESH : Mice, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Neoplasm Invasiveness, MESH : Lung Neoplasms, MESH: Intercellular Signaling Peptides and Proteins, MESH : Capillary Permeability, MESH: Mice, MESH : Intercellular Signaling Peptides and Proteins, 030304 developmental biology, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, Intravasation, MESH: Capillary Permeability, Actin cytoskeleton, medicine.disease, MESH: Lung Neoplasms, Mice, Inbred C57BL, biology.protein, Cancer research, MESH : Animals, Lymph Nodes, Angiopoietins, MESH: Female
Abstract

Angiopoietin-like 4 (ANGPTL4), a secreted protein of the angiopoietin-like family, is induced by hypoxia in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers. Here, we investigated whether ANGPTL4 might affect tumor growth as well as metastasis. Metastatic 3LL cells were therefore xenografted into control mice and mice in which ANGPTL4 was expressed by using in vivo DNA electrotransfer. Whereas primary tumors grew at a similar rate in both groups, 3LL cells metastasized less efficiently to the lungs of mice that expressed ANGPTL4. Fewer 3LL emboli were observed in primary tumors, suggesting that intravasation of 3LL cells was inhibited by ANGPTL4. Furthermore, melanoma B16F0 cells injected into the retro-orbital sinus also metastasized less efficiently in mice expressing ANGPTL4. Although B16F0 cells were observed in lung vessels, they rarely invaded the parenchyma, suggesting that ANGPTL4 affects extravasation. In addition, recombinant B16F0 cells that overexpress ANGPTL4 were generated, showing a lower capacity for in vitro migration, invasion, and adhesion than control cells. Expression of ANGPTL4 induced reorganization of the actin cytoskeleton through inhibition of actin stress fiber formation and vinculin localization at focal contacts. Together, these results show that ANGPTL4, through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness.

Published
2006
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8. Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell adhesion, migration, and sprouting and alters actin cytoskeleton

Author

Nicolas Bréchot, Ariane Galaup, Clémence Chomel, Laurent Muller, Marine Bignon, Stéphane Germain, Catherine Monnot, Pierre Corvol, Aurélie Cazes, Holger Weber, Sébastien Le Jan, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Vascular Biology and Angiogenesis Research, Tumor Biology Center, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Mouret, Sandrine, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hématologie A [CHU HEGP], and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
MESH: Heparin, MESH : Biological Availability, Physiology, Angiogenesis, MESH: Anoxia, MESH : Actins, Extracellular matrix, MESH : Cytoskeleton, Mice, 0302 clinical medicine, Cell Movement, Ischemia, MESH: Blood Proteins, MESH : Cell Movement, MESH: Animals, MESH: Endothelial Cells, Hypoxia, Cytoskeleton, MESH: Cell Movement, Cells, Cultured, MESH: Biological Availability, Tube formation, 0303 health sciences, MESH : Neovascularization, Physiologic, MESH: Hindlimb, MESH : Extracellular Matrix, Blood Proteins, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Proteoglycans, Extracellular Matrix, Hindlimb, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Endothelial stem cell, Biochemistry, 030220 oncology & carcinogenesis, MESH: Proteoglycans, Proteoglycans, Cardiology and Cardiovascular Medicine, MESH: Neovascularization, Physiologic, MESH: Cells, Cultured, MESH : Blood Proteins, MESH : Anoxia, Biological Availability, Neovascularization, Physiologic, MESH : Mice, Inbred C57BL, Angiopoietin-like 4 Protein, In Vitro Techniques, Biology, MESH: Extracellular Matrix, MESH: Actins, Article, MESH: Cell Adhesion, Angiopoietin, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Ischemia, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cells, Cultured, Cell Adhesion, MESH: Cytoskeleton, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Angiopoietin-Like Protein 4, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH : Hindlimb, MESH : Endothelial Cells, Heparin, Endothelial Cells, Actin cytoskeleton, Actins, Mice, Inbred C57BL, MESH : Cell Adhesion, MESH : Heparin, MESH : Animals, MESH: Ischemia, Angiopoietins
Abstract

Angiopoietin-like 4 (ANGPTL4) is a secreted protein that belongs to the angiopoietin family and is involved in angiogenesis and metabolism regulation. We previously reported the induction of angptl4 by hypoxia in endothelial cells and in human ischemic tissues from peripheral artery disease. We here observed in a mouse model of hindlimb ischemia that the mRNA upregulation in the vessels correlates with the accumulation of the full-length protein in ischemic tissues. We then investigated its functions in endothelial cells. In response to hypoxia, endogenous ANGPTL4 accumulates in the subendothelial extracellular matrix (ECM). Although the secreted protein undergoes proteolysis leading to truncated fragments present in the medium, only full-length ANGPTL4 interacts with the ECM. Competition and direct binding assays indicate that the strong interaction of ANGPTL4 with the ECM is heparin/heparan sulfate proteoglycan dependent. The balance between matrix-associated and soluble forms of ANGPTL4 points to the role of the ECM in the regulation of its bioavailability. The angiogenic function of the ECM-bound full-length protein was investigated using either the form associated with the conditioned ECM from ANGPTL4-transfected HEK293 cells or the purified immobilized protein. We show that matrix-associated and immobilized ANGPTL4 limit the formation of actin stress fibers and focal contacts in the adhering endothelial cells and inhibit their adhesion. Immobilized ANGPTL4 also decreases motility of endothelial cells and inhibits the sprouting and tube formation. Altogether, these findings show that hypoxic endothelial cells accumulate ANGPTL4 in the ECM, which in turn negatively regulates their angiogenic capacities through an autocrine pathway.

Published
2006
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9. Akt Down-Regulates ERK1/2 Nuclear Localization and Angiotensin II-induced Cell Proliferation through PEA-15

Author

Gervais, Marianne, Dugourd, Céline, Muller, Laurent, Ardidie, Corinne, Canton, Brigitte, Loviconi, Laetitia, Corvol, Pierre, Chneiweiss, Herve, Monnot, Catherine, York, John, Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Verlaine - Metz (UPVM), Neurobiologie pharmacologique, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Neuropharmacologie (INSERM U114), Collège de France (CdF (institution)), Mouret, Sandrine, and Collège de France - Chaire Neuropharmacologie (INSERM U114)

Subjects
MAPK/ERK pathway, Transcription, Genetic, AKT1, MESH: Cricetinae, MESH: Down-Regulation, 0302 clinical medicine, Cricetinae, MESH: Animals, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Kinase, MESH: Proto-Oncogene Proteins c-fos, Angiotensin II, Intracellular Signaling Peptides and Proteins, food and beverages, Articles, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell biology, Protein Transport, 030220 oncology & carcinogenesis, MESH: Angiotensin II, Proto-Oncogene Proteins c-fos, MESH: Mitogen-Activated Protein Kinase 3, Half-Life, Protein Binding, MESH: Cells, Cultured, MESH: Half-Life, MESH: Mitogen-Activated Protein Kinase 1, MESH: Cell Nucleus, MESH: Protein Transport, MESH: Rats, Down-Regulation, CHO Cells, Biology, MESH: Phosphoproteins, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: CHO Cells, MESH: Cell Proliferation, MESH: Intracellular Signaling Peptides and Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, MESH: Protein Binding, MESH: ets-Domain Protein Elk-1, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, ets-Domain Protein Elk-1, 030304 developmental biology, Cell Nucleus, Angiotensin II receptor type 1, MESH: Humans, Cell growth, MESH: Proto-Oncogene Proteins c-akt, MESH: Transcription, Genetic, Cell Biology, Phosphoproteins, Molecular biology, Rats, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt
Abstract

International audience; Angiotensin II (AngII) type 1 receptors (AT1) regulate cell growth through the extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol 3-kinase (PI3K) pathways. ERK1/2 and Akt/protein kinase B, downstream of PI3K, are independently activated but both required for mediating AngII-induced proliferation when expressed at endogenous levels. We investigate the effect of an increase in the expression of wild-type Akt1 by using Chinese hamster ovary (CHO)-AT1 cells. Unexpectedly, Akt overexpression inhibits the AT1-mediated proliferation. This effect could be generated by a cross-talk between the PI3K and ERK1/2 pathways. A functional partner is the phosphoprotein enriched in astrocytes of 15 kDa (PEA-15), an Akt substrate known to bind ERK1/2 and to regulate their nuclear translocation. We report that Akt binds to PEA-15 and that Akt activation leads to PEA-15 stabilization, independently of PEA-15 interaction with ERK1/2. Akt cross-talk with PEA-15 does not affect ERK1/2 activation but decreases their nuclear activity as a result of the blockade of ERK1/2 nuclear accumulation. In response to AngII, PEA-15 overexpression displays the same functional consequences on ERK1/2 signaling as Akt overactivation. Thus, Akt overactivation prevents the nuclear translocation of ERK1/2 and the AngII-induced proliferation through interaction with and stabilization of endogenous PEA-15.

Published
2006
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10. Characterization of the expression of the hypoxia-induced genes neuritin, TXNIP and IGFBP3 in cancer

Author

Stéphane Germain, Sébastien Le Jan, Jean J. Leger, Martine Le Cunff, Pierre Corvol, Josette Philippe, Aurélie Cazes, Nolwenn Le Meur, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), SLJ is a recipient of both Ministère de la Recherche and Fondation pour la Recherche Médicale fellowships. AC is a recipient of an INSERM fellowship. SG is supported by grants from la Fondation de France and Canceropole-PACA ACI 2004 and belongs to the Eu, Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -IFR26-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and Mouret, Sandrine

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Angiogenesis, medicine.medical_treatment, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, angiogenesis, Thioredoxins, 0302 clinical medicine, Endothelial cell, Structural Biology, Neoplasms, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Cells, Cultured, In Situ Hybridization, 0303 health sciences, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, endothelial cells, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Gene Expression Regulation, Neoplastic, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], tumor markers, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], TXNIP, Biophysics, [SDV.CAN]Life Sciences [q-bio]/Cancer, In situ hybridization, Biology, GPI-Linked Proteins, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Humans, Tumor marker, Northern blot, Molecular Biology, 030304 developmental biology, Tumor microenvironment, hypoxia, Growth factor, Neuropeptides, Cell Biology, Insulin-Like Growth Factor Binding Protein 3, Cancer research, gene expression, Representational difference analysis, Carrier Proteins
Abstract

International audience; By triggering an adaptive response to hypoxia which is a common feature of tumor microenvironments, endothelial cells contribute to the onset of angiogenic responses involved in tumor growth. Therefore, identifying hypoxic markers represent a challenge for a better understanding of tumor angiogenesis and for the optimization of anti-angiogenic therapeutic strategy. Using representational difference analysis combined with microarray, we here report the identification of 133 hypoxia-induced transcripts in human microendothelial cells (HMEC-1). By Northern blot, we confirm hypoxia-induced expression of insulin-like growth factor binding protein 3 (igfbp3), thioredoxin-interacting protein (txnip), neuritin (nrn1). Finally, by performing in situ hybridization on several types of human tumors, we provide evidence for nrn1 and txnip as hypoxic perinecrotic markers and for igfbp3 as a tumor endothelial marker. We propose these hypoxia-induced genes could represent relevant prognostic tools and targets for therapeutic intervention in cancers.

Published
2006
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11. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus

Author

Xavier Jeunemaitre, Alain Lalande, Jean-Baptiste Michel, Philippe Khau Van Kien, Limin Zhu, Mark Wegman, François Brunotte, Nicolas Boisset, Patrick Bruneval, Roger Vranckx, Flavie Mathieu, Jean-Eric Wolf, Luke Glancy, Jean-Marie Gasc, Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CDF), Collège de France (CdF), Sch Med, Ruijin Hosp, French Chinese Genom Pole, Shanghai Jiao Tong University [Shanghai], Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Faculté de Médecine Xavier Bichat, Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale (LPPCE), Université de Bourgogne (UB), Service de cardiologie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de RMN Spectroscopie, Médecine Nucléaire (CHU de Dijon), Lab Elect & Informat Image, Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Hlth Sci Ctr, Dept Med, Cardiol Sect, Louisiana State University (LSU), Service d'anatomo-pathologie [CHU HEGP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Centre d'Investigation Clinique - Epidemiologie Clinique/essais Cliniques de l'Hopital Europeen Georges Pompidou, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Collège de France ( CDF ), Collège de France ( CdF ), Shanghai Jiao Tong Univ, Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université Paris Diderot - Paris 7 ( UPD7 ), Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale ( LPPCE ), Université de Bourgogne ( UB ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre National de la Recherche Scientifique ( CNRS ), Institut de minéralogie et de physique des milieux condensés ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IPG PARIS-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Louisiana State Univ, Service d'anatomo-pathologie [HEGP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Ruijin Hospital, French Chinese Genomic Pole, Shanghai Jiao Tong University School of Medicine, Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHU de Dijon], Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Section of Cardiology, Department of Medicine, Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France (CDF (laboratoire)), Collège de France (CdF (institution)), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Cardiologie II, Centre Hospitalier Universitaire, Centre d'Imagerie par Résonance Magnétique, Centre Hospitalier Universitaire, Laboratoire Electronique, Informatique et Image [UMR6303] ( Le2i ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-École Nationale Supérieure d'Arts et Métiers ( ENSAM ), Louisiana State University Health Sciences Center New Orleans, Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire Electronique, Informatique et Image ( Le2i ), and Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Adult, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Molecular Sequence Data, ANEURYSM/DISSECTION, 030204 cardiovascular system & hematology, Biology, Thoracic aortic aneurysm, Protein Structure, Secondary, DISEASE, Familial thoracic aortic aneurysm, COILED-COILS, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Ductus arteriosus, Genetics, medicine, MYH11, LOCUS, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Ductus Arteriosus, Patent, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Aortic dissection, 0303 health sciences, Aortic Aneurysm, Thoracic, Base Sequence, Myosin Heavy Chains, SMC protein, HEAVY-CHAIN ISOFORMS, Anatomy, medicine.disease, Pedigree, Aortic Dissection, medicine.anatomical_structure, Mutation, biology.protein, cardiovascular system, Female, ACTA2, SMOOTH-MUSCLE MYOSIN
Abstract

We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection ( TAAD) and patent ductus arteriosus (PDA)(1,2) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocalization of wild-type and mutant rod proteins in SMC, in conjunction with differences in their coimmunoprecipitation capacities, strongly suggest a dominant-negative effect. Human MYH11 gene mutations provide the first example of a direct change in a specific SMC protein leading to an inherited arterial disease.

Published
2006
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12. Is oxygen a key factor in the lipodystrophy phenotype?

Author

Stéphane Germain, Sébastien Le Jan, Pierre Sonigo, C. Gentil, Jacques Leibowitch, Josette Philippe, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche et d'applications sur les thérapies géniques (CRATG), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)-Généthon, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité d'Immuno-Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service d'hématologie A [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by the Ensemble Contre le Sida- SIDACTION Foundation., Germain, Stéphane, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche et d'applications sur les thérapies géniques ( CRATG ), Université d'Évry-Val-d'Essonne ( UEVE ) -GENETHON 3-Centre National de la Recherche Scientifique ( CNRS ), Pathologie vasculaire et endocrinologie rénale, Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches], and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )

Subjects
Leptin, MESH : Oxygen, Endocrinology, Diabetes and Metabolism, MESH: Somatostatin, Clinical Biochemistry, MESH: Anoxia, Peroxisome proliferator-activated receptor, Adipose tissue, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, ANGPTL4, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH : DNA, Mitochondrial, Adipocyte, MESH : Tri, Hypoxia, MESH : Reverse Transcriptase Inhibitors, lcsh:RC620-627, Cells, Cultured, chemistry.chemical_classification, 0303 health sciences, Adipogenesis, MESH : Somatostatin, MESH : Gene Expression Regulation, HIV-Associated Lipodystrophy Syndrome, MESH : Adipogenesis, MESH: Gene Expression Regulation, 3. Good health, MESH : Phenotype, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lcsh:Nutritional diseases. Deficiency diseases, Phenotype, Adipose Tissue, Biochemistry, 030220 oncology & carcinogenesis, MESH : Leptin, MESH: Oligopeptides, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Reverse Transcriptase Inhibitors, Lipodystrophy, medicine.symptom, Somatostatin, Oligopeptides, MESH: Adipose Tissue, MESH: Oxygen, MESH: Cells, Cultured, MESH : PPAR gamma, MESH : Oligopeptides, medicine.medical_specialty, MESH : Anoxia, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Phenotype, MESH : Adipose Tissue, DNA, Mitochondrial, Peptides, Cyclic, 03 medical and health sciences, MESH: Tri, Internal medicine, MESH : Cells, Cultured, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Triglycerides, 030304 developmental biology, MESH: HIV-Associated Lipodystrophy Syndrome, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Research, MESH : Humans, Biochemistry (medical), MESH : HIV-Associated Lipodystrophy Syndrome, MESH: DNA, Mitochondrial, MESH: Leptin, Hypoxia (medical), medicine.disease, Oxygen, PPAR gamma, Gene Expression Regulation, chemistry, MESH: PPAR gamma, MESH: Reverse Transcriptase Inhibitors, MESH: Adipogenesis
Abstract

BackgroundThe lipodystrophic syndrome (LD) is a disorder resulting from selective damage of adipose tissue by antiretroviral drugs included in therapy controlling human-immunodeficiency-virus-1. In the therapy cocktail the nucleoside reverse transcriptase inhibitors (NRTI) contribute to the development of this syndrome. Cellular target of NRTI was identified as the mitochondrial polymerase-gamma and their toxicity described as a mitochondrial DNA (mtDNA) depletion resulting in a mitochondrial cytopathy and involved in fat redistribution. No mechanisms offer explanation whatsoever for the lipo-atrophic and lipo-hypertrophic phenotype of LD. To understand the occurrence we proposed that the pO2 (oxygen partial pressure) could be a key factor in the development of the LD. For the first time, we report here differential effects of NRTIs on human adipose cells depending on pO2 conditions.Results and discussionWe showed that the hypoxia conditions could alter adipogenesis process by modifying expression of adipocyte makers as leptin and the peroxisome proliferator-activated receptor PPARgamma and inhibiting triglyceride (TG) accumulation in adipocytes. Toxicity of NRTI followed on adipose cells in culture under normoxia versus hypoxia conditions showed, differential effects of drugs on mtDNA of these cells depending on pO2 conditions. Moreover, NRTI-treated adipocytes were refractory to the inhibition of adipogenesis under hypoxia. Finally, our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat.ConclusionToxicity of NRTIs have been shown to be opposite on human adipose cells depending on the oxygen availability. These data suggest that the LD phenotype may be a differential consequence of NRTI effects, depending on the metabolic status of the targeted adipose tissues and provide new insights into the opposite effects of antiretroviral treatment, as observed for the lipo-atrophic and lipo-hypertrophic phenotype characteristic of LD.

Published
2006
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13. Angiopoietin-like 4-Induced 3D Capillary Morphogenesis Correlates to Stabilization of Endothelial Adherens Junctions and Restriction of VEGF-Induced Sprouting

Author

Athanasia Liabotis, Corinne Ardidie-Robouant, Philippe Mailly, Samaher Besbes, Charly Gutierrez, Yoann Atlas, Laurent Muller, Stéphane Germain, Catherine Monnot, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
angiopoietin-like 4, vascular endothelial growth factor, angiogenesis, adherens junction, in vitro 3D model, vascularization, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), C angiopoietin-like 4, General Biochemistry, Genetics and Molecular Biology
Abstract

Angiopoietin-like 4 (ANGPTL4) is a target of hypoxia that accumulates in the endothelial extracellular matrix. While ANGPTL4 is known to regulate angiogenesis and vascular permeability, its context-dependent role related to vascular endothelial growth factor (VEGF) has been suggested in capillary morphogenesis. We here thus develop in vitro 3D models coupled to imaging and morphometric analysis of capillaries to decipher ANGPTL4 functions either alone or in the presence of VEGF. ANGPTL4 induces the formation of barely branched and thin endothelial capillaries that display linear adherens junctions. However, ANGPTL4 counteracts VEGF-induced formation of abundant ramified capillaries presenting cell–cell junctions characterized by VE-cadherin containing reticular plaques and serrated structures. We further deciphered the early angiogenesis steps regulated by ANGPTL4. During the initial activation of endothelial cells, ANGPTL4 alone induces cell shape changes but limits the VEGF-induced cell elongation and unjamming. In the growing sprout, ANGPTL4 maintains cohesive VE-cadherin pattern and sustains moderate 3D cell migration but restricts VEGF-induced endothelium remodeling and cell migration. This effect is mediated by differential short- and long-term regulation of P-Y1175-VEGFR2 and ERK1-2 signaling by ANGPTL4. Our in vitro 3D models thus provide the first evidence that ANGPTL4 induces a specific capillary morphogenesis but also overcomes VEGF effect.

Published
2021
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14. Extracellular matrix scaffolding in angiogenesis and capillary homeostasis

Author

Stéphane Germain, Marion Marchand, Catherine Monnot, Laurent Muller, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Scaffold, Angiogenesis, [SDV]Life Sciences [q-bio], Morphogenesis, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Basement Membrane, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Collagen XVIII, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, Basement membrane, Membrane Glycoproteins, Neovascularization, Pathologic, biology, Endothelial Cells, Cell Biology, Collagen Type XVIII, Extracellular Matrix, Fibronectins, Cell biology, [SDV] Life Sciences [q-bio], Fibronectin, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Blood Vessels, Laminin, Pericytes, Heparan Sulfate Proteoglycans, 030217 neurology & neurosurgery, Homeostasis, Developmental Biology
Abstract

The extracellular matrix (ECM) of blood vessels, which is composed of both the vascular basement membrane (BM) and the interstitial ECM is identified as a crucial component of the vasculature. We here focus on the unique molecular composition and scaffolding of the capillary ECM, which provides structural support to blood vessels and regulates properties of endothelial cells and pericytes. The major components of the BM are collagen IV, laminins, heparan sulfate proteoglycans and nidogen and also associated proteins such as collagen XVIII and fibronectin. Their organization and scaffolding in the BM is required for proper capillary morphogenesis and maintenance of vascular homeostasis. The BM also regulates vascular mechanosensing. A better understanding of the mechanical and structural properties of the vascular BM and interstitial ECM therefore opens new perspectives to control physiological and pathological angiogenesis and vascular homeostasis. The overall aim of this review is to explain how ECM scaffolding influences angiogenesis and capillary integrity.

Published
2019
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15. Aminopeptidase A, generating one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, plays a key role in central control of blood pressure

Author

Rozenfeld, Raphael, Reaux, Annabelle, Xavier Iturrioz, Fassot, Celine, Fournie-Zaluski, Marie-Claude, David, Christelle, Maigret, Bernard, Roques, Bernard Pierre, Corvol, Pierre, Llorens-Cortes, Catherine, INSERM U36, Collège de France (CdF), Collège de France, INSERM U266, Fassot, Céline, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), and Collège de France (CdF (institution))

Subjects
Male, Models, Molecular, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Blood Pressure, CD13 Antigens, Crystallography, X-Ray, Glutamyl Aminopeptidase, Rats, Inbred WKY, Renin-Angiotensin System, Mice, Methionine, Rats, Inbred SHR, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Sulfhydryl Compounds, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, Brain Chemistry, Binding Sites, Angiotensin II, Angiotensin III, Rats, Drug Design, Mutagenesis, Site-Directed, Sulfonic Acids
Abstract

International audience

Published
2020

16. VEGF-A plasma levels are associated with microvascular obstruction in patients with ST-segment elevation myocardial infarction

Author

Giuseppina Caligiuri, Corinne Ardidie-Robouant, Stéphane Germain, Damien Logeart, Claire Bouleti, Marc Sirol, Rodrigue Garcia, Jean-Jacques Mercadier, Catherine Monnot, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Percutaneous Coronary Intervention, Internal medicine, medicine, ST segment, Humans, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Prospective Studies, 10. No inequality, Aged, Ejection fraction, medicine.diagnostic_test, biology, business.industry, Microcirculation, Percutaneous coronary intervention, Magnetic resonance imaging, Middle Aged, medicine.disease, Troponin, Coronary Occlusion, No reflow phenomenon, biology.protein, Cardiology, ST Elevation Myocardial Infarction, Female, Cardiology and Cardiovascular Medicine, business, human activities, TIMI, Biomarkers, Follow-Up Studies
Abstract

Background Microvascular obstruction (MVO) is associated with poor outcome after ST-segment elevation myocardial infarction (STEMI). Vascular endothelial growth factor-A (VEGF-A) is a vascular permeability inducer playing a key role in MVO pathogenesis. We aimed to assess whether VEGF-A levels are associated with MVO, when evaluated by magnetic resonance imaging (MRI) in STEMI patients. Methods The multicenter prospective PREGICA study included a CMR substudy with all consecutive patients with a first STEMI who had undergone cardiac MRI at baseline and at 6-month follow-up. Patients with initial TIMI flow >1 were excluded. VEGF-A levels were measured in blood samples drawn at inclusion. Results Between 2010 and 2017, 147 patients (mean age 57 ± 10 years; 84% males) were included. MVO was present in 65 (44%) patients. After multivariate analysis, higher troponin peak (OR 1.005; 95% CI 1.001–1.008; p = 0.007) and VEGF-A levels (OR 1.003; 95% CI 1.001–1.005; p = 0.015) were independently associated with MVO. When considering only patients with successful percutaneous coronary intervention (final TIMI flow 3, n = 130), higher troponin peak (p = 0.004) and VEGF-A levels (p = 0.03) remained independently predictive of MVO. Moreover, MVO was associated with adverse left ventricular (LV) remodeling and VEGF-A levels were significantly and inversely correlated with LV ejection fraction (EF) at 6-month follow-up. Conclusion Our results show that VEGF-A levels were independently associated with MVO during STEMI and correlated with mid-term LVEF alteration. VEGF-A could therefore be considered as a biomarker of MVO in STEMI patients and be used to stratify patient prognosis.

Published
2019
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17. Phostine 3.1a as a pharmacological compound with antiangiogenic properties against diseases with excess vascularization

Author

Sylvain Recoquillon, Naïg Gueguen, M. Carmen Martinez, Morgane Le Mao, Luisa Vergori, Guy Lenaers, Ludovic Clarion, Ramaroson Andriantsitohaina, Marion Marchand, Raffaella Soleti, Stéphane Germain, Norbert Bakalara, Simon Bousseau, Grégory Hilairet, Salim Khiati, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Angiogénèse embryonnaire et pathologique, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Male, Vascular Endothelial Growth Factor A, Galectin 1, Angiogenesis, [SDV]Life Sciences [q-bio], Angiogenesis Inhibitors, Apoptosis, Biochemistry, chemistry.chemical_compound, Mice, angiogenesis, pharmacotherapy, 0302 clinical medicine, Adenosine Triphosphate, Glycomimetic, Cell Movement, Zebrafish, ComputingMilieux_MISCELLANEOUS, Tube formation, Neovascularization, Pathologic, Chemistry, Adhesion, 3. Good health, Extracellular Matrix, Adenosine Diphosphate, Biotechnology, Signal Transduction, Glycosylation, glycosylation, Phosphines, Mice, Nude, cancer growth, 03 medical and health sciences, endothelial metabolism, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Cell Line, Tumor, Genetics, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Animals, Humans, Molecular Biology, Cell Proliferation, Endothelial Cells, Metabolism, Vascular Endothelial Growth Factor Receptor-2, In vitro, 030104 developmental biology, Cancer research, Glioblastoma, 030217 neurology & neurosurgery, Neoplasm Transplantation
Abstract

International audience; Angiogenesis is a complex process leading to the growth of new blood vessels from existing vasculature, triggered by local proangiogenic factors such as VEGF. An excess of angiogenesis is a recurrent feature of various pathologic conditions such as tumor growth. Phostines are a family of synthetic glycomimetic compounds that exhibit anticancer properties, and the lead compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST 3.1a) shows antiglioblastoma properties both in vitro and in vivo. In the present study, we assessed the effect of PST 3.1a on angiogenesis and endothelial metabolism. In vitro, PST 3.1a (10 µM) inhibited all steps that regulate angiogenesis, including migration, proliferation, adhesion, and tube formation. In vivo, PST 3.1a reduced intersegmental vessel formation and vascularization of the subintestinal plexus in zebrafish embryos and also altered pathologic angiogenesis and glioblastoma progression in vivo. Mechanistically, PST 3.1a altered interaction of VEGF receptor 2 and glycosylation-regulating protein galectin-1, a key component regulating angiogenesis associated with tumor resistance. Thus, these data show that use of PST 3.1a is an innovative approach to target angiogenesis.-Bousseau, S., Marchand, M., Soleti, R., Vergori, L., Hilairet, G., Recoquillon, S., Le Mao, M., Gueguen, N., Khiati, S., Clarion, L., Bakalara, N., Martinez, M. C., Germain, S., Lenaers, G., Andriantsitohaina, R. Phostine 3.1a as a pharmacological compound with antiangiogenic properties against diseases with excess vascularization.

Published
2019
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18. [PD-L1 testing in non-small cell lung carcinoma: Guidelines from the PATTERN group of thoracic pathologists]

Author

Sylvie, Lantuejoul, Julien, Adam, Nicolas, Girard, Mickael, Duruisseaux, Audrey, Mansuet-Lupo, Aurélie, Cazes, Isabelle, Rouquette, Laure, Gibault, Stéphane, Garcia, Martine, Antoine, Jean Michael, Vignaud, Françoise, Galateau-Sallé, Christine, Sagan, Cécile, Badoual, Frédérique, Penault-Llorca, Diane, Damotte, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Interactions cellulaires tumorales et leur environnement et réponse aux agents anti-cancéreux, Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Anatomy-Pathology Hôpital Nord Laënnec, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service de chirurgie thoracique et d'anatomopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel Dieu, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
PD-L1, Lung Neoplasms, Organoplatinum Compounds, Quality Assurance, Health Care, Recommandations, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guidelines, B7-H1 Antigen, Specimen Handling, Antineoplastic Agents, Immunological, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Randomized Controlled Trials as Topic, Cancer, Patient Selection, Immunohistochimie, Immunohistochemistry, Neoplasm Proteins, Poumon, Clinical Trials, Phase III as Topic, Reagent Kits, Diagnostic, Lung cancer, Algorithms
Abstract

International audience; Lung cancer is the leading cause of cancer death in France with low response rates to conventional chemotherapy. Nevertheless, new therapies have emerged recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab (OPDIVO®, Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®, Merck & Co), or PD-L1 ICI, such as atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, Astra-Zeneca), and avelumab (BAVENCIO®, EMD Serono). The prescription of pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients requires the demonstration of PD-L1 expression by tumor cells by immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is now considered as a companion diagnostic tool for this drug. Numerous standardized PD-L1 assays performed on dedicated platforms have been validated in clinical trials, each antibody being associated to one specific PD1 or PD-L1 inhibitor. However, not all pathologists have access to the dedicated platforms and the high cost of these assays is still a limitation to their implementation; in addition, the small size of the NSCLC tumor samples does not allow to perform at the same time multiple assays for multiple drugs. The use of laboratory-developed tests seems feasible but their validation must guarantee the same sensitivities and specificities as standardized tests. In this context, the French group of thoracic pathologists PATTERN has teamed up with thoracic oncologists to provide recommendations on the indication, the critical technical steps and the interpretation of the PD-L1 IHC test to help pathologists to implement quickly and in the best conditions this new theranostic test.

Published
2018
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19. Angiopoietin-like 4 serum levels on admission for acute myocardial infarction are associated with no-reflow

Author

Philippe Cluzel, Philippe Gabriel Steg, Catherine Monnot, Jean Michel Serfaty, Gilles Montalescot, Stéphane Germain, Thomas Mathivet, Elodie Berland, Claire Bouleti, Nicolas Vignolles, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
medicine.medical_specialty, medicine.diagnostic_test, biology, Troponin T, business.industry, medicine.medical_treatment, C-reactive protein, Percutaneous coronary intervention, Odds ratio, Anterior Descending Coronary Artery, medicine.disease, 3. Good health, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiac magnetic resonance imaging, Internal medicine, No reflow phenomenon, cardiovascular system, medicine, biology.protein, Cardiology, cardiovascular diseases, Myocardial infarction, Cardiology and Cardiovascular Medicine, business
Abstract

Background No-reflow in ST-segment elevation acute myocardial infarction (STEMI) is associated with a poor clinical prognosis. Its pathophysiological mechanisms are not fully elucidated yet but enhanced vascular permeability plays a key role in this phenomenon. Angiopoietin-like 4 (ANGPTL4) has been implicated in vascular permeability in experimental models of acute myocardial infarction (AMI). We therefore sought to investigate whether baseline ANGPTL4 serum levels are associated with no-reflow after primary percutaneous coronary intervention (PPCI). Methods We studied a group of 41 patients presenting with a first STEMI within 12h of onset of symptoms and who underwent successful PPCI. Blood samples were obtained from all patients on admission before the start of the procedure, for ANGPTL4 level measurement. No-reflow was assessed by cardiac magnetic resonance imaging (MRI), the reference method. Results MRI-detected no-reflow was observed in 20 patients (48.8%). Variables independently associated with no-reflow on multivariate logistic regression analysis were: lower ANGPTL4 serum levels (odds ratio 0.82, 95% CI 0.70–0.98, P =0.02), higher troponin T peak (odds ratio 1.03, 95% CI 1.00–1.05, P =0.03), higher incidence of left anterior descending coronary artery (LAD) as culprit artery (odds ratio 14.61, 95% CI 1.24–172.49, P =0.03), and higher C-reactive protein levels (odds ratio 1.18, 95% CI 1.00–1.39, P =0.05). Conclusion ANGPTL4 serum levels predict MRI-detected no-reflow after successful PPCI in STEMI patients. Given the recently demonstrated therapeutic role of ANGPTL4 in diminishing no-reflow and limiting infarct size in pre-clinical animal models, these findings in humans may open up new possibilities in the field of research.

Published
2015
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20. A chicken model of pharmacologically-induced Hirschsprung disease reveals an unexpected role of glucocorticoids in enteric aganglionosis

Author

Maud Clemessy, Jean-Marie Gasc, Hervé Kempf, Pierre Corvol, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, Hirschsprung disease, QH301-705.5, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Endothelin, chemistry.chemical_compound, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology (General), Glucocorticoids, [SDV.BA]Life Sciences [q-bio]/Animal biology, Phosphoramidon, Neural crest, Embryo, Phenotype, Penetrance, 3. Good health, chemistry, Cancer research, Chick embryo, Enteric nervous system, General Agricultural and Biological Sciences, Endothelin receptor, Congenital megacolon, Research Article
Abstract

International audience; The enteric nervous system originates from neural crest cells that migrate in chains as they colonize the embryonic gut, eventually forming the myenteric and submucosal plexus. Failure of the neural crest cells to colonize the gut leads to aganglionosis in the terminal gut, a pathological condition called Hirschsprung disease (HSCR) in humans, also known as congenital megacolon or intestinal aganglionosis. One of the characteristics of the human HSCR is its variable penetrance, which may be attributable to the interaction between genetic factors, such as the endothelin-3/endothelin receptor B pathway, and non-genetic modulators, although the role of the latter has not well been established. We have created a novel HSCR model in the chick embryo allowing to test the ability of non-genetic modifiers to alter the HSCR phenotype. Chick embryos treated by phosphoramidon, which blocks the generation of endothelin-3, failed to develop enteric ganglia in the very distal bowel, characteristic of an HSCR-like phenotype. Administration of dexamethasone influenced the phenotype, suggesting that glucocorticoids may be environmental modulators of the penetrance of the aganglionosis in HSCR disease.

Published
2015
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21. ANGPTL4, a multifaceted protein at the cross-talk between metabolism and cardiovascular disorders

Author

Catherine Monnot, Claire Bouleti, Stéphane Germain, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
business.industry, 030204 cardiovascular system & hematology, medicine.disease, Bioinformatics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiovascular Diseases, ANGPTL4, 030220 oncology & carcinogenesis, Angiopoietin-Like Protein 4, Medicine, Risk factor, Cardiology and Cardiovascular Medicine, business, Angiopoietins, Stroke
Abstract

We read with interest the letter from Fei Luo et al. Indeed, whether developing therapeutic agents aimed at long-term blocking ANGPTL4 is a matter of intense debate.

Published
2018
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22. Coupling between Myogenesis and Angiogenesis during Skeletal Muscle Regeneration Is Stimulated by Restorative Macrophages

Author

Cyril Gitiaux, Bénédicte Chazaud, Fabrice Chrétien, Michèle Weiss-Gayet, Mélanie Magnan, Pascal Leblanc, Laurent Muller, Stéphane Germain, Sabrina Ben-Larbi, Claire Latroche, Rana Abou-Khalil, Rémi Mounier, Sophie Liot, Nicolas Verger, Paul Bardot, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was funded by INSERM, CNRS, Université Paris Descartes, and Université Claude Bernard Lyon 1, by EU FP7 Endostem (no. 241440), and by Association Française contre les Myopathies (grant no. 18003). C.L. was supported by Dim Stem Pole from Région Ile-de-France and Association Française contre les Myopathies. R.A.-K. was supported by Association Française contre les Myopathies. C.G. was supported by a Poste d'Accueil APHP/CNRS. We thank AniRA-Cytometry facility from SFR Biosciences, Université Claude Bernard Lyon 1, and Genom'ic facility from Institut Cochin, European Project: 241440,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,ENDOSTEM(2010), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), KARLI, Mélanie, Activation of vasculature associated stem cells and muscle stem cells for the repair and maintenance of muscle tissue - ENDOSTEM - - EC:FP7:HEALTH2010-01-01 - 2014-12-31 - 241440 - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Verlaine - Metz (UPVM), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physiologie-Biologie du Sport, Université d'Auvergne - Clermont-Ferrand I (UdA), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut Mondor de recherche biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Angiogenesis, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Muscle Development, Biochemistry, Myoblasts, Mice, angiogenesis, 0302 clinical medicine, Cell Movement, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Gene Expression Regulation, Developmental, MESH: Animals, lcsh:QH301-705.5, MESH: Cell Movement, ComputingMilieux_MISCELLANEOUS, Endothelial Progenitor Cells, lcsh:R5-920, MESH: Muscle, Skeletal, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Myogenesis, Stem Cells, Oncostatin M, MESH: Regeneration, Gene Expression Regulation, Developmental, Cell Differentiation, Cell biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], macrophages, medicine.anatomical_structure, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Cell Adhesion Molecules, Apelin, MESH: Muscle Development, myogenesis, Stem cell, lcsh:Medicine (General), MESH: Neovascularization, Physiologic, MESH: Cell Differentiation, Neovascularization, Physiologic, MESH: Stem Cells, Periostin, Biology, Article, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], skeletal muscle regeneration, Genetics, medicine, Animals, Humans, Regeneration, MESH: Myoblasts, Progenitor cell, Muscle, Skeletal, MESH: Mice, Wound Healing, MESH: Humans, Regeneration (biology), Skeletal muscle, MESH: Macrophages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, MESH: Blood Vessels, MESH: Oncostatin M, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, MESH: Wound Healing, 030104 developmental biology, muscle stem cells, MESH: Endothelial Progenitor Cells, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Apelin, biology.protein, Blood Vessels, Cell Adhesion Molecules, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology
Abstract

Summary In skeletal muscle, new functions for vessels have recently emerged beyond oxygen and nutrient supply, through the interactions that vascular cells establish with muscle stem cells. Here, we demonstrate in human and mouse that endothelial cells (ECs) and myogenic progenitor cells (MPCs) interacted together to couple myogenesis and angiogenesis in vitro and in vivo during skeletal muscle regeneration. Kinetics of gene expression of ECs and MPCs sorted at different time points of regeneration identified three effectors secreted by both ECs and MPCs. Apelin, Oncostatin M, and Periostin were shown to control myogenesis/angiogenesis coupling in vitro and to be required for myogenesis and vessel formation during muscle regeneration in vivo. Furthermore, restorative macrophages, which have been previously shown to support myogenesis in vivo, were shown in a 3D triculture model to stimulate myogenesis/angiogenesis coupling, notably through Oncostatin M production. Our data demonstrate that restorative macrophages orchestrate muscle regeneration by controlling myogenesis/angiogenesis coupling., Graphical Abstract, Highlights • Endothelial cells (ECs) promote myogenesis • Myogenic progenitor cells (MPCs) stimulate angiogenesis as they differentiate • EC- and MPC-derived Apelin, Oncostatin M, and Periostin promote myo-angiogenesis • Restorative macrophages stimulate myo-angiogenesis via Oncostatin M secretion, In this study, Chazaud et al. demonstrate that endothelial cells (ECs) and myogenic progenitor cells (MPCs) interacted to couple myogenesis and angiogenesis during skeletal muscle regeneration. EC- and MPC-derived Apelin, Oncostatin M, and Periostin controlled myogenesis/angiogenesis coupling and were required for myogenesis and vessel formation. They show that, via the production of Oncostatin M, restorative macrophages promoted myogenesis/angiogenesis coupling.

Published
2017
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23. ANGPTL4-αvβ3 interaction counteracts hypoxia-induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2

Author

Bryan M Robb, Gavin Thurston, Elisa Gomez Perdiguero, George D. Yancopoulos, Michel Paques, Sylvie Ricard-Blum, Athanasia Liabotis-Fontugne, Ariane Galaup, David M. Valenzuela, Stéphane Germain, Mélanie Durand, Clément Faye, Sébastien Augustin, Andrew J. Murphy, Manuel Simonutti, Catherine Monnot, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Angiogenesis, Knockout, [SDV]Life Sciences [q-bio], Vascular permeability, Angiopoietin-like 4 Protein, Biology, Retina, Pathology and Forensic Medicine, Adherens junction, Capillary Permeability, Mice, 03 medical and health sciences, 0302 clinical medicine, VE-cadherin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Angiopoietin-Like Protein 4, Animals, Humans, Phosphorylation, vascular permeability, Mice, Knockout, Integrin alphaVbeta3, hypoxia, angiopoietin-like 4, integrin αvβ3, Kinase insert domain receptor, Vascular Endothelial Growth Factor Receptor-2, Cell Hypoxia, Choroidal Neovascularization, 3. Good health, Cell biology, Vascular endothelial growth factor B, 030104 developmental biology, src-Family Kinases, VEGFR2, hypoxia vascular permeability angiopoietin-like 4 VEGFR2 integrin αvβ3 VE-cadherin, Angiopoietins, 030217 neurology & neurosurgery, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction
Abstract

Dynamic control of endothelial cell junctions is essential for vascular homeostasis and angiogenesis. We recently provided genetic evidence that ANGPTL4 is a key regulator of vascular integrity both during developmental and in hypoxia-induced pathological conditions. The purpose of the present study was to decipher the molecular mechanisms through which ANGPTL4 regulates vascular integrity. Using surface plasmon resonance and proximity ligation assays, we show that ANGPTL4 binds integrin αvβ3. In vitro and in vivo functional assays with Angptl4-deficient mice demonstrate that ANGPTL4-αvβ3 interaction is necessary to mediate ANGPTL4 vasoprotective effects. Mechanistically, ANGPTL4-αvβ3 interaction enhances Src recruitment to integrin αvβ3 and inhibits Src signalling downstream of vascular endothelial growth factor receptor 2 (VEFGR2), thereby repressing hypoxia-induced breakdown of VEGFR2-VE-cadherin and VEGFR2-αvβ3 complexes. We further demonstrate that intravitreal injection of recombinant human ANGPTL4 limits vascular permeability and leads to increased adherens junction and tight junction integrity. These findings identify a novel mechanism by which ANGPTL4 counteracts hypoxia-driven vascular permeability through integrin αvβ3 binding, modulation of VEGFR2-Src kinase signalling, and endothelial junction stabilization. We further demonstrate that Angptl4-deficient mice show increased vascular leakage in vivo in a model of laser-induced choroidal neovascularization, indicating that this newly identified ANGPTL4-αvβ3 axis might be a target for pharmaceutical intervention in pathological conditions. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2016
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24. Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4

Author

Stéphane Germain, Anne Janin, Aurélie Cazes, Mélanie Durand, Claire Bouleti, Sébastien Le Jan, Alain Berdeaux, Gaëlle Briois, Jérémie Teillon, Renaud Tissier, Bijan Ghaleh, Gavin Thurston, Philippe Bonnin, George D. Yancopoulos, Valérie Martin, David M. Valenzuela, Andrew J. Murphy, Rana Assaly, Catherine Monnot, Sandrine Pons, Philippe Ratajczak, Rachid Souktani, Josette Philippe, Ariane Galaup, Elisa Gomez, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
Male, Pathology, medicine.medical_specialty, Cardiotonic Agents, Endothelium, Myocardial Infarction, Mice, Transgenic, Inflammation, Vascular permeability, Angiopoietin-like 4 Protein, 030204 cardiovascular system & hematology, Angiopoietin, Mice, Random Allocation, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Edema, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Myocytes, Cardiac, cardiovascular diseases, Myocardial infarction, Cells, Cultured, 030304 developmental biology, Mice, Knockout, 0303 health sciences, business.industry, Kinase insert domain receptor, medicine.disease, Mice, Inbred C57BL, medicine.anatomical_structure, cardiovascular system, No-Reflow Phenomenon, Endothelium, Vascular, Rabbits, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Angiopoietins
Abstract

Background— Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell–cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results— We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4 -deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4 -deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4 -deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions— These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.

Published
2012
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25. Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane

Author

Cathy Pichol-Thievend, Stéphane Germain, Florence Ruggiero, Nicholas Brechot, Michel Caron, Laurent Muller, Emilie Guillon, Julie Hardouin, Marine Bignon, Eric Etienne, A. Barret, Luiz Nasciutti, Marilyne Malbouyres, Jérémie Teillon, Raymonde Joubert-Caron, Catherine Monnot, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Collagen Type IV, Angiogenesis, Immunology, Neovascularization, Physiologic, Lysyl oxidase, Biology, Biochemistry, Basement Membrane, Cell Line, Extracellular matrix, Mice, 03 medical and health sciences, Type IV collagen, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell Movement, medicine, Animals, Humans, Zebrafish, 030304 developmental biology, Basement membrane, Sprouting angiogenesis, 0303 health sciences, LOXL2, Endothelial Cells, Cell Biology, Hematology, Zebrafish Proteins, Molecular biology, Cell Hypoxia, Extracellular Matrix, Up-Regulation, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Basal lamina, Amino Acid Oxidoreductases, Endothelium, Vascular
Abstract

Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding.

Published
2011
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26. Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma

Author

Laurent Muller, Pierre Corvol, Geneviève Nguyen, Aurelie Contrepas, Diane Bracquart, Christelle Cousin, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Cytoplasm, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Fluorescent Antibody Technique, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, CHO Cells, 030204 cardiovascular system & hematology, Biology, Transfection, Polymerase Chain Reaction, Sensitivity and Specificity, 03 medical and health sciences, Cricetulus, 0302 clinical medicine, Cricetinae, Internal medicine, Renin, Internal Medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Receptor, Furin, Cells, Cultured, Embryonic Stem Cells, Probability, 030304 developmental biology, mRNA Cleavage and Polyadenylation Factors, ATP6AP2, Analysis of Variance, 0303 health sciences, Metalloproteinase, Protease, Chinese hamster ovary cell, In vitro, Rats, Endocrinology, Solubility, biology.protein
Abstract

International audience; The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for α1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-α protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.

Published
2009
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27. Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice

Author

Philippe Bonnin, Evelyne Dupuy, Noël Lamandé, Jean-Marie Gasc, Patricia Hainaud, François Vincent, Maud Clemessy, Pierre Corvol, José Vilar, Gérard Tobelem, Jean-Olivier Contreres, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Explorations Fonctionnelles Physiologiques [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Cancer Research, Angiogenesis, Angiotensinogen, Metastasis, Neovascularization, Mice, MESH: Liver Neoplasms, Experimental, Liver Neoplasms, Experimental, 0302 clinical medicine, MESH: Animals, Receptor, Notch4, 0303 health sciences, Neovascularization, Pathologic, Receptors, Notch, Intracellular Signaling Peptides and Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, 3. Good health, Liver, Oncology, 030220 oncology & carcinogenesis, MESH: Cell Growth Processes, Female, MESH: Membrane Proteins, medicine.symptom, hormones, hormone substitutes, and hormone antagonists, Genetically modified mouse, medicine.medical_specialty, MESH: Mice, Transgenic, Transgene, MESH: Angiotensinogen, Ephrin-B2, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Growth Processes, Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, In vivo, Proto-Oncogene Proteins, MESH: Intracellular Signaling Peptides and Proteins, Internal medicine, Renin–angiotensin system, medicine, Animals, Humans, RNA, Messenger, MESH: Mice, Adaptor Proteins, Signal Transducing, MESH: RNA, Messenger, 030304 developmental biology, MESH: Ephrin-B2, MESH: Humans, Calcium-Binding Proteins, Membrane Proteins, medicine.disease, MESH: Male, Mice, Inbred C57BL, MESH: Proto-Oncogene Proteins, Endocrinology, Tumor progression, MESH: Neovascularization, Pathologic, MESH: Receptors, Notch, MESH: Female, MESH: Liver
Abstract

Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo. [Cancer Res 2009;69(7):2853–60]

Published
2009
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28. Distribution of cells expressing human renin-promoter activity in the brain of a transgenic mouse

Author

Stéphane Germain, Erin L. O'Callaghan, L. Hazelwood, J. Schnermann, Hayo Castrop, Andrew M. Allen, Jaspreet K. Bassi, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
Genetically modified mouse, Transgene, Mice, Transgenic, Nerve Tissue Proteins, Deep cerebellar nuclei, Renin-Angiotensin System, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genes, Reporter, Renin, Renin–angiotensin system, Animals, Humans, Nuclear protein, Promoter Regions, Genetic, Receptor, Molecular Biology, 030304 developmental biology, Neurons, Regulation of gene expression, Brain Mapping, 0303 health sciences, Receptors, Angiotensin, biology, General Neuroscience, Brain, Nuclear Proteins, beta-Galactosidase, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Lac Operon, biology.protein, Neurology (clinical), NeuN, Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Renin plays a critical role in fluid and electrolyte homeostasis by cleaving angiotensinogen to produce Ang peptides. Whilst it has been demonstrated that renin mRNA is expressed in the brain, the distribution of cells responsible for this expression remains uncertain. We have used a transgenic mouse approach in an attempt to address this question. A transgenic mouse, in which a 12.2 kb fragment of the human renin promoter was used to drive expression of Cre-recombinase, was crossed with the ROSA26- lac Z reporter mouse strain. Cre-recombinase mediated excision of the floxed stop cassette resulted in expression of the reporter protein, β-galactosidase. This study describes the distribution of β-galactosidase in the brain of the crossed transgenic mouse. In all cases where it was examined the reporter protein was co-localized with the neuronal marker NeuN. An extensive distribution was observed with numerous cells labeled in the somatosensory, insular, piriform and retrosplenial cortices. The motor cortex was devoid of labeled cells. Several other regions were labeled including the parts of the amygdala, periaqueductal gray, lateral parabrachial nucleus and deep cerebellar nuclei. Overall the distribution shows little overlap with those regions that are known to express receptors for the renin–angiotensin system in the adult brain. This transgenic approach, which demonstrates the distribution of cells which have activated the human renin promoter at any time throughout development, yields a unique and extensive distribution of putative renin-expressing neurons. Our observations suggest that renin may have broader actions in the brain and may indicate a potential for interaction with the (pro)renin receptor or production of a ligand for non-AT 1 /AT 2 receptors.

Published
2008
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29. Reciprocal Regulation of Plasma Apelin and Vasopressin by Osmotic Stimuli

Author

Xavier Iturrioz, Séverine Peyrard, Anne Blanchard, Nicolas Chartrel, Nadia De Mota, Hubert Vaudry, Catherine Llorens-Cortes, Pierre Corvol, Michel Azizi, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CIC AP-HP (hegp Ex-Broussais)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Iturrioz, Xavier, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre interdisciplinaire de recherche en biologie (CIRB), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Llorens Cortes, Catherine

Subjects
Male, Vasopressin, MESH: Renin, [SDV]Life Sciences [q-bio], MESH: Saline Solution, Hypertonic, MESH: Arginine Vasopressin, MESH: Body Fluids, Electrolytes, MESH: Osmolar Concentration, 0302 clinical medicine, MESH: Electrolytes, Renin, [CHIM] Chemical Sciences, Blood plasma, MESH: Blood Proteins, Homeostasis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, Chemistry, Blood Proteins, General Medicine, Water-Electrolyte Balance, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Body Fluids, Apelin, [SDV] Life Sciences [q-bio], Hematocrit, MESH: Homeostasis, Nephrology, Intercellular Signaling Peptides and Proteins, MESH: Drinking, hormones, hormone substitutes, and hormone antagonists, Adult, medicine.medical_specialty, Adolescent, Drinking, MESH: Hematocrit, 03 medical and health sciences, Clinical Research, Osmotic Pressure, Internal medicine, Renin–angiotensin system, medicine, Humans, [CHIM]Chemical Sciences, MESH: Intercellular Signaling Peptides and Proteins, 030304 developmental biology, Saline Solution, Hypertonic, MESH: Adolescent, MESH: Humans, Osmolar Concentration, MESH: Adult, MESH: Osmotic Pressure, MESH: Male, Hypertonic saline, Arginine Vasopressin, Plasma osmolality, Endocrinology, nervous system, MESH: Water-Electrolyte Balance, Magnocellular cell, 030217 neurology & neurosurgery
Abstract

International audience; Apelin is a neuropeptide that co-localizes with vasopressin (AVP) in magnocellular neurons and is involved in body fluid homeostasis. Osmotic stimuli have opposite effects on the regulation of apelin and AVP secretion in animal models, but whether this is true in humans is unknown. This study investigated the relationship among osmolality, apelin, and AVP in 10 healthy men after infusion of hypertonic saline or loading with water to increase and decrease plasma osmolality, respectively. Increasing plasma osmolality was accompanied by a parallel, linear increase in plasma AVP concentration and by a decrease in plasma apelin concentration. In contrast, decreasing plasma osmolality by water loading reduced plasma AVP concentration and rapidly increased plasma apelin concentration. These findings suggest that regulation of apelin secretion contributes to the maintenance of body fluid homeostasis.

Published
2008
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30. Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

Author

Frank Antonicelli, Sébastien Le Jan, Guy Haegeman, Meriem Riani, Anne Durlach, Richard Le Naour, J. Plée, Philippe Bernard, Genetique des Maladies Vasculaires, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Adaptative et Fonctionnalité des Barrières Biologiques - EA 4683 (IMAB), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), Department of Physiology, Universiteit Gent = Ghent University [Belgium] (UGENT), Direction de la recherche, Société des accumulateurs fixes et de traction (SAFT), Université de Reims Champagne-Ardenne (URCA), Service de dermatologie (CHU de Reims), Centre Hospitalier Universitaire de Reims (CHU Reims), and Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC)

Subjects
0301 basic medicine, Male, Chemokine, Neutrophils, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Monocytes, 030207 dermatology & venereal diseases, 0302 clinical medicine, Glucocorticoid receptor, Blister, Pemphigoid, Bullous, Immunology and Allergy, Lymphocytes, skin and connective tissue diseases, Cells, Cultured, selective glucocorticoid receptor activator, Skin, Aged, 80 and over, medicine.diagnostic_test, biology, integumentary system, CXCL10, autoimmunity, Middle Aged, 3. Good health, Cytokine, Matrix Metalloproteinase 9, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bullous pemphigoid, Immunology, Cell Line, 03 medical and health sciences, Immune system, medicine, Humans, Aged, Autoimmune disease, compound A, business.industry, medicine.disease, Chemokine CXCL10, 030104 developmental biology, inflammation, Skin biopsy, biology.protein, business
Abstract

International audience; Background: The outcome of bullous pemphigoid (BP), the most frequent autoimmune skin-blistering disease, involves matrix metalloproteinase 9 (MMP-9), IL-17, and IL-23 release from infiltrated inflammatory cells. The chemokine CXCL10 has been associated with several autoimmune diseases, but its participation in BP pathophysiology still needs to be clarified. Objective: We sought to assess whether BP outcome was associated with different CXCL10 levels and to evaluate the contribution of CXCL10 to the described cytokine/protease inflammatory loop associated with disease outcome. Methods: Skin biopsy specimens (n 5 16), serum (n 5 114), blister fluid (n 5 23), and primary inflammatory cells from patients with BP were used to investigate CXCL10 expression and function. Results: At baseline, both resident cells, such as keratinocytes and fibroblasts, and infiltrating immune cells expressed CXCL10 at lesional sites in skin of patients with BP. CXCL10 levels were higher in blister fluid (P < .0001) and serum (P < .005) from patients with BP than in serum from age-and sex-matched control subjects (n 5 34). Furthermore, CXCL10 serum levels increased at day 60 only in patients who relapsed within the first year of treatment (n 5 33, P < .005). Interestingly, CXCL10 expression could be upregulated by itself and IL-17 in inflammatory cells. Notably, neutrophils and monocytes from patients with BP, but not lymphocytes, responded to CXCL10 by increasing MMP-9 secretion through the activation of extracellular signal-regulated kinase 1/2, p38, phosphoinositide-3 kinase signaling pathways. Finally, CXCL10-increased MMP-9 secretion was inhibited by methylprednisolone and also by compound A, a novel nonsteroidal glucocorticoid receptor ligand. Conclusion: We showed that increased levels of inflammatory biomarkers in patients with BP, such as CXCL10, favor neutrophil-and monocyte-associated MMP-9 release and disease relapse and opened new therapeutic horizons in patients with this autoimmune disease.

Published
2016
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31. No-reflow et microvascularisation coronaire : une victime collatérale de la reperfusion de l'infarctus du myocarde

Author

S. Germain, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Germain, Stéphane

Subjects
03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, business.industry, Medicine, 030212 general & internal medicine, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

International audience

Published
2016

32. Expression Pattern of Prokineticin 1 and Its Receptors in Bovine Ovaries During the Estrous Cycle: Involvement in Corpus Luteum Regression and Follicular Atresia

Author

Aharon Friedman, Rina Meidan, Eyal Klipper, Nadia Alfaidy, Tatiana Kisliouk, Dieter Schams, Qun-Yong Zhou, Department of Pharmacology [Irvine], University of California [Irvine] (UCI), University of California-University of California, Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Vascular Endothelial Growth Factor A, medicine.medical_specialty, Follicular Atresia, Cell Count, Estrous Cycle, Biology, Luteal phase, Ceramides, Dinoprost, Monocytes, Receptors, G-Protein-Coupled, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Corpus Luteum, Internal medicine, Luteolysis, Escherichia coli, medicine, Animals, Cholesterol Side-Chain Cleavage Enzyme, Receptor, 030304 developmental biology, Estrous cycle, 0303 health sciences, 030219 obstetrics & reproductive medicine, Follicular atresia, Ovary, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, General Medicine, Flow Cytometry, Immunohistochemistry, Prokineticin, Vascular endothelial growth factor, medicine.anatomical_structure, Endocrinology, Reproductive Medicine, chemistry, Cattle, Female, Vascular Endothelial Growth Factor, Endocrine-Gland-Derived, Corpus luteum
Abstract

International audience; Prokineticin 1 (PROK1), also termed endocrine gland-derived vascular endothelial growth factor (endocrine gland-derived VEGF), is a newly identified protein assigned with diverse biologic functions. It binds two homologous G protein-coupled receptors, PROKR1 and PROKR2. To better understand the roles of PROK1 and its receptors in ovarian function, their expression was determined in follicles and corpora lutea (CLs) at different developmental stages. PROK1 mRNA levels were low at early luteal stage and midluteal stage, but increased sharply during natural or induced luteolysis. High PROK1 mRNA levels also were found in atretic follicles. This profile of PROK1 expression was opposite to that of the well-established angiogenic factor VEGF. Of the two receptor-type expressions, PROKR1 but not PROKR2 was correlated positively with its ligand. Immunohistochemical staining revealed that PROK1 was located mainly within the muscular layer of arterioles, and during regression it also was localized to macrophages and steroidogenic cells. The expression pattern of ITGB2 mRNA, a leukocyte cell marker, overlapped that of PROK1, thus suggesting that leukocyte infiltration may explain the elevated expression of PROK1 in atretic follicles and regressing CL. Indeed, flow cytometry analyses showed that nearly all beta-2 integrin chain (ITGB2)-positive cells also were stained with anti-PROK1 and that significantly more ITGB2/PROK1 double-stained cells were present in degenerating follicles and CL. Furthermore, when challenged in vitro with PROK1, adherent, mononuclear cell numbers and TNF levels were elevated, indicating that PROK1 triggers monocyte activation. Together, these data suggest that PROK1, acting via PROKR1, may be involved in the recruitment of monocytes to regressing CL and atretic follicles and their consequent activation therein.

Published
2007
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33. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion

Author

Rümeyza Bascetin, Gaël Y. Rochefort, Antonino Nicoletti, Didier Letourneur, Carmen Marchiol, Anne Poliard, Laurent Muller, Benjamin Salmon, Caroline Gorin, Pascal Merlet, Benoit Hosten, Dominique Le-Denmat, Julie Lesieur, Stéphane Germain, Sarah Berndt, Hanru Ying, Anita Novais, Laetitia Vercellino, Sibylle Vital, Matthieu Lesage, Jérémy Sadoine, Nathan Beckouche, Catherine Chaussain, Pathologies, Imagerie et Biothérapies oro-faciales (EA 2496), Université Paris Descartes - Paris 5 (UPD5), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologies, Imagerie et Biothérapies oro-faciales ( EA 2496 ), Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP), Centre interdisciplinaire de recherche en biologie ( CIRB ), Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Plateforme Imagerie du Vivant, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Collège de France ( CdF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service de Médecine Nucléaire [Saint-Louis], AP-HP Hôpital Saint-Louis, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Recherche Vasculaire Translationnelle ( LVTS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Odontologie [Bretonneau], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bretonneau, Université Paris Descartes - Faculté de Chirurgie Dentaire ( UPD5 Odontologie ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bretonneau, Université Paris Descartes - Faculté de Chirurgie Dentaire (UPD5 Odontologie), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bretonneau, Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF)-PSL Research University (PSL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Verlaine - Metz (UPVM), Pathologie vasculaire et endocrinologie rénale, Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sadoine, Jérémy

Subjects
0301 basic medicine, Mesenchymal Stem Cells -- drug effects -- metabolism, Vascular Endothelial Growth Factor A, Angiogenesis, Fibroblast growth factor, chemistry.chemical_compound, Dental Pulp -- cytology, Hypoxia, ComputingMilieux_MISCELLANEOUS, Hepatocyte growth factor, Pulp engineering, Hepatocyte Growth Factor, General Medicine, Sciences bio-médicales et agricoles, Cell Hypoxia, Cell biology, Vascular endothelial growth factor, Vascular endothelial growth factor A, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Fibroblast Growth Factor 2, Stem cell, medicine.drug, Hepatocyte Growth Factor -- biosynthesis -- metabolism, Neovascularization, Physiologic, Fibroblast Growth Factor 2 -- administration & dosage -- biosynthesis, Biology, Mesenchymal Stem Cell Transplantation, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, stomatognathic system, Dental pulp stem cells, Tissue Engineering and Regenerative Medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Dynamic vascular imaging, Progenitor cell, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Neovascularization, Physiologic -- genetics, Dental Pulp, Tissue Engineering, Mesenchymal Stem Cells, Cell Biology, Cell Hypoxia -- drug effects, Vascular Endothelial Growth Factor A -- biosynthesis -- metabolism, [ SDV.IB.BIO ] Life Sciences [q-bio]/Bioengineering/Biomaterials, [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, stomatognathic diseases, 030104 developmental biology, chemistry, Immunology, Mesenchymal stem cells, Developmental Biology
Abstract

Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF., info:eu-repo/semantics/published

Published
2015
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34. Heterodimerization of Endothelin-converting Enzyme-1 Isoforms Regulates the Subcellular Distribution of This Metalloprotease

Author

Eric Etienne, Laurent Muller, Olivier Valdenaire, R Meidan, C Tougard, Pierre Corvol, A. Barret, Müller, Laurent, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Dynamins, Gene isoform, Signal peptide, Endosome, Endothelin converting enzyme 1, Recombinant Fusion Proteins, Molecular Sequence Data, Endosomes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Endothelin-Converting Enzymes, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Extracellular, Animals, Aspartic Acid Endopeptidases, Amino Acid Sequence, Enzyme Inhibitors, education, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, 0303 health sciences, education.field_of_study, Metalloendopeptidases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Transfection, Acetylcysteine, Anti-Bacterial Agents, Protein Structure, Tertiary, Cell biology, Isoenzymes, Cytosol, Pituitary Gland, Mutagenesis, Site-Directed, Macrolides, Dimerization, 030217 neurology & neurosurgery, Intracellular
Abstract

International audience; Endothelin-converting enzyme (ECE) is a membrane metalloprotease that generates endothelin from its direct precursor big endothelin. Four isoforms of ECE-1 are produced from a single gene through the use of alternate promoters. These isoforms share the same extracellular catalytic domain and contain unique cytosolic tails, which results in their specific subcellular targeting. We investigated the distribution of ECE-1 isoforms in transfected AtT-20 neuroendocrine cells. Whereas ECE-1a and 1c were present at the plasma membrane, ECE-1b and ECE-1d were retained inside the cells. We found that both intracellular isoforms were concentrated in the endosomal system: ECE-1d in recycling endosomes, and ECE-1b in late endosomes/multivesicular bodies. Leucine-based motifs were involved in the intracellular retention of these isoforms, and the targeting of ECE-1b to the degradation pathway required an additional signal in the N terminus. The concentration of ECE-1 isoforms in the endosomal system suggested new functions for these enzymes. Potential novel functions include redistribution of other isoforms through direct interaction. We have showed that ECE-1 isoforms could heterodimerize, and that in such heterodimers the ECE-1b targeting signal was dominant. Interaction of a plasma membrane isoform with ECE-1b resulted in its intracellular localization and decreased its extracellular activity. These data demonstrated that the targeting signals specific for ECE-1b constitute a regulatory domain per se that could modulate the localization and the activity of other isoforms.

Published
2003
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35. Stem cells increase in numbers in perinecrotic areas in human renal cancer

Author

Arnaud Duval, Christophe Leboeuf, Jérôme Verine, Niclas Setterblad, Anne Janin, Guillaume Gapihan, Jean-Paul Feugeas, Pierre Mongiat-Artus, Irmine Ferreira, Philippe Ratajczak, Guilhem Bousquet, Mariana Varna, Sophie Tan, Stéphane Germain, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pathologie (Sorbonne Paris Cité / UNIV Paris Diderot), Université Paris Diderot, Sorbonne Paris Cité, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), and Germain, Stéphane

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Indoles, Necrosis, Mice, Nude, Antineoplastic Agents, urologic and male genital diseases, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Renal cell carcinoma, Cancer stem cell, Sunitinib, medicine, Animals, Humans, Pyrroles, Carcinoma, Renal Cell, 030304 developmental biology, 0303 health sciences, business.industry, Therapeutic effect, Hypoxia (medical), medicine.disease, Xenograft Model Antitumor Assays, Kidney Neoplasms, In vitro, female genital diseases and pregnancy complications, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, medicine.symptom, Stem cell, business, medicine.drug
Abstract

Purpose: Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis–associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. Experimental Design: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4–coexpressing cells derived from the two responder xenograft models were used for in vitro studies. Results: In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4–coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. Conclusions: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. Clin Cancer Res; 21(4); 916–24. ©2014 AACR.

Published
2015
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36. Expression of endothelins in human cardiogenesis

Author

Hervé Kempf, Marcus Brand, Jean-Marie Gasc, Pierre Corvol, Martin Paul, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Heart Defects, Congenital, Heart Septal Defects, Ventricular, medicine.hormone, medicine.medical_specialty, 030310 physiology, Cellular differentiation, Aorta, Thoracic, Branchial arch, In situ hybridization, Endothelin-Converting Enzymes, In Vitro Techniques, Biology, Gene Expression Regulation, Enzymologic, Endothelins, 03 medical and health sciences, Fetal Heart, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Drug Discovery, medicine, Aspartic Acid Endopeptidases, Humans, Myocyte, RNA, Messenger, Heart formation, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, Endothelin-2, 0303 health sciences, Endothelin-1, Gene Expression Regulation, Developmental, Metalloendopeptidases, Neural crest, [SDV.BDD.MOR]Life Sciences [q-bio]/Development Biology/Morphogenesis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Endocrinology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, cardiovascular system, Molecular Medicine, Female, Endothelin receptor
Abstract

Genetic disruption of endothelin (ET) 1, endothelin-converting enzyme (ECE) 1, and endothelin receptor A (ET(A)) in "knockout" or mutant mouse models result in defects in branchial arch derived craniofacial tissues and in cardiac outflow and great vessel structures. Interestingly, certain types of human congenital cardiovascular malformations such as Catch 22 syndrome and type B interruption of the aortic arch strongly resemble defects seen in knockout animal models. To better address the exact involvement of the ET system in heart formation we explored the spatiotemporal pattern of expression of the components of the ET system during critical phases of cardiogenesis in the human embryo (3-6 weeks of development; Carnegie stages 10-17) by in situ hybridization. We detected high ET-1 mRNA expression in endocardial cells lining the heart outflow tract in the region where the future aortic valves will form. No hybridization signal corresponding to pre-pro-ET-3 was observed in the heart. At the same location, the underlying myocytes express ET(A) mRNA. Whereas a functional role of ET in the valve formation can be proposed because of the simultaneous presence of all the components of the endothelin system (ET-1/ECE-1/ET(A)), this seems not to be the case for the formation of the ventricular septum where endocardial cells do not express ET-1, and only a weak ET(A) hybridization signal was detected in the surrounding myocardium. An abnormal hemodynamism indirectly due to valve malformation may be the indirect cause of this septal defect. The results of this study suggest an important role for the ET system in the formation of certain anatomical structures of the developing human heart.

Published
2002
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37. Expression of Renin in Large Arteries Outside the Kidney Revealed by Human Renin Promoter/LacZ Transgenic Mouse

Author

Sebastien Fuchs, Josette Philippe, Pierre Corvol, Stéphane Germain, Florence Pinet, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Genetically modified mouse, medicine.medical_specialty, Afferent arterioles, Transgene, Mice, Transgenic, 030204 cardiovascular system & hematology, Biology, Kidney, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Renin, Renin–angiotensin system, medicine, Animals, Humans, Promoter Regions, Genetic, 030304 developmental biology, 0303 health sciences, Arteries, Animal Models, Juxtaglomerular apparatus, beta-Galactosidase, Angiotensin II, medicine.anatomical_structure, Endocrinology, Lac Operon, Interlobular arteries
Abstract

International audience; Renin plays a central role in controlling blood pressure as it catalyzes the first step in the production of angiotensin II. The aim of this study was to isolate fragments of the human renin (hREN) promoter able to direct tissue-specific and regulated expression of a LacZ reporter gene mimicking endogenous renin. We screened several hREN promoter/LacZ constructs for transgene expression in transient embryos at E15 when renin expression begins. We found that a 12-kb hREN promoter conferred high expression in the kidney at both embryonic and adult stages and that the transgene was expressed in the same cells as endogenous renin. We explored two pathophysiological models in which renin is stimulated and showed concomitant increases in beta-galactosidase and renin activities. In situ beta-galactosidase staining showed renin/transgene-expressing cells are recruited in the juxtaglomerular apparatus and in the afferent arterioles as well as in larger arteries outside the kidney. Using our model, renin expression in interlobular arteries was confirmed as being striped and, for the first time, expression of renin in larger arteries outside the kidney was shown. Therefore, this strain is a suitable model to investigate renin gene pathophysiological regulations in vivo.

Published
2002
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38. ANGIOPOIETIN-LIKE 4 SERUM LEVELS ON ADMISSION FOR ACUTE MYOCARDIAL INFARCTION ARE ASSOCIATED WITH NO-REFLOW ASSESSED BY MAGNETIC RESONANCE IMAGING

Author

Jean Michel Serfaty, Stéphane Germain, Thomas Mathivet, Claire Bouleti, Elodie Berland, Philippe Gabriel Steg, Nicolas Vignolles, Gilles Montalescot, Philippe Cluzel, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, medicine.disease, Angiopoietin, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Cardiology, cardiovascular system, Myocardial infarction, cardiovascular diseases, business, Cardiology and Cardiovascular Medicine
Abstract

No-reflow in ST-segment elevation acute myocardial infarction (STEMI) is associated with a poor clinical prognosis. Its pathophysiologal mechanisms are not totally elucidated yet but enhanced vascular permeability plays a key role in this process. Angiopoietin-Like 4 (ANGPTL4) has been implicated in

Published
2014
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39. New Elements In Human Renin Promoter Involved In Cell-Specific Expression

Author

Josette Philippe, Pierre Corvol, Sebastien Fuchs, Stéphane Germain, Florence Pinet, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Genetically modified mouse, Physiology, Mice, Transgenic, Biology, Kidney, Mice, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genes, Reporter, In vivo, Physiology (medical), Renin, Renin–angiotensin system, medicine, Animals, Humans, Promoter Regions, Genetic, 030304 developmental biology, Pharmacology, 0303 health sciences, Reporter gene, 030302 biochemistry & molecular biology, Gene Expression Regulation, Developmental, Promoter, Transfection, Embryo, Mammalian, Molecular biology, medicine.anatomical_structure, Organ Specificity, Ex vivo
Abstract

International audience; 1. The renin-angiotensin system plays a major role in blood pressure regulation and electrolyte homeostasis through the action of angiotensin (Ang) II. The first and rate-limiting step in the production of AngII is the conversion of angiotensinogen into AngI, which is catalysed by the aspartyl protease renin (EC 3.4.23.15). Circulating active renin is mainly synthesized, processed and secreted by the juxtaglomerular cells within the kidney. 2. To determine the renin 5'-flanking sequences involved in cell and tissue specificity, ex vivo and in vivo studies were performed. Several constructs of various lengths of renin promoter linked to the luciferase gene were first tested ex vivo by transfection in primary cultures of human chorionic cells. The constructs giving a high and specific expression in renin-producing cells were then tested in vivo in a transgenic mice model. 3. The reporter gene chosen to generate transgenic mice was LacZ and the screening was performed in embryos at the embryonic day (E) 15 stage, at which mouse renin is expressed in the developing vessels of the kidney. 4. Only constructs containing more than 5.7 kb of the human renin promoter lead to specific expression of beta-galactosidase in the kidney. 5. Our results demonstrate that the human renin distal promoter region allows a more restricted expression of LacZ in the renin-expressing cells in transgenic mice.

Published
2001
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40. Pulmonary endothelinergic system in experimental congestive heart failure

Author

Paul Mulder, Monique Philippe, Delphine Lepailleur-Enouf, Jean-Paul Henry, Liliane Louedec, Giorgia Egidy, Jean-Baptiste Michel, U 460, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Physiology, [SDV]Life Sciences [q-bio], heart failure, receptors, Endothelin-Converting Enzymes, 030204 cardiovascular system & hematology, Endothelins, 0302 clinical medicine, Aspartic Acid Endopeptidases, Endothelial dysfunction, Lung, Aorta, 0303 health sciences, Endothelin-1, Receptors, Endothelin, Metalloendopeptidases, Peptide secretion, Receptor, Endothelin A, Receptor, Endothelin B, 3. Good health, medicine.anatomical_structure, cardiovascular system, Cardiology, Cardiology and Cardiovascular Medicine, Endothelin receptor, medicine.hormone, medicine.medical_specialty, Heart Ventricles, Diastole, 03 medical and health sciences, Organ Culture Techniques, Physiology (medical), Internal medicine, medicine, Animals, RNA, Messenger, Protein Precursors, Rats, Wistar, Muscle, Skeletal, 030304 developmental biology, Analysis of Variance, business.industry, medicine.disease, Endothelin 1, Rats, Pleural Effusion, Endocrinology, Heart failure, gene expression, endothelins, business
Abstract

International audience; Objectives: Endothelin-1 (ET-1), plays an important role in the pathophysiology of CHF and the pulmonary endothelium is an early hemodynamic target in diastolic left ventricular dysfunction. Therefore we hypothesized that the lung is a main source of humoral endothelin in CHF and that its secretion is proportional to the degree of heart failure. Methods and results: We used rats with coronary artery ligation as an experimental model of either compensated or decompensated heart failure, depending on infarct size. Reverse transcriptase polymerase chain reaction (RT-PCR) revealed that in the lung, the expression of preproET-1 mRNA was higher in decompensated HF than in control and compensated HF rats (P

Published
2001
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41. The endothelin system in normal human colon

Author

Fred T. Bosman, Giorgia Egidy, Lucienne Juillerat-Jeanneret, Florence Pinet, Petra Korth, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Pathology, and Centre Hospitalier Universitaire Vaudois (CHUV)

Subjects
Male, Physiology, [SDV]Life Sciences [q-bio], Gene Expression, Endothelin-Converting Enzymes, Iodine Radioisotopes, Endothelins, immunocytochemistry, Nerve Fibers, 0302 clinical medicine, Aspartic Acid Endopeptidases, Receptor, In Situ Hybridization, Aged, 80 and over, 0303 health sciences, Endothelin-1, Receptors, Endothelin, Gastroenterology, Metalloendopeptidases, Middle Aged, Receptor, Endothelin A, Receptor, Endothelin B, Endothelial stem cell, medicine.anatomical_structure, 030220 oncology & carcinogenesis, endothelial cell, Female, Endothelin receptor, Neuroglia, Adult, medicine.hormone, medicine.medical_specialty, Colon, Immunocytochemistry, In situ hybridization, Biology, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Humans, Endothelium, RNA, Messenger, Protein Precursors, smooth muscle cell, Aged, 030304 developmental biology, Lamina propria, Hepatology, Macrophages, Muscle, Smooth, Endothelin 1, Molecular biology, Endocrinology, Biomarkers
Abstract

Endothelin (ET)-1 is a potent vasoconstrictor and mitogenic peptide that has a variety of biological effects in noncardiovascular tissues. The precise cellular distribution of the ET-1 system in the wall of the normal human colon was studied to identify the physiological role of ET in the gut. In situ hybridization revealed ET-converting enzyme-1 (ECE-1) mRNA in all vessels, the colon epithelium, and macrophages. Prepro-ET-1 (PPET-1) mRNA had a similar distribution except for a scattered signal in mucosal microvessels. ETAand ETBreceptor mRNAs were mainly in the lamina propria, pericryptal myofibroblasts, microvessels, and mononuclear cells, with ETAmRNA more abundant than ETBmRNA.125I-ET-1 binding showed ETBalong the crypts and in nerve fibers descending from the ganglionic plexus that contained PPET-1, ECE-1, and ETBtranscripts, whereas glia contained ETAreceptors. The finding of the entire ET system in the normal mucosa suggests its implication in some characteristic functions of the colon and its secretion as both a neuroactive and a vasoactive peptide.

Published
2000
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42. Histidine 450 Plays a Critical Role in Catalysis and, with Ca2+, Contributes to the Substrate Specificity of Aminopeptidase A

Author

Gilles Vazeux, Xavier Iturrioz, Catherine Llorens-Cortes, Jérôme Célérier, Pierre Corvol, Iturrioz, Xavier, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV]Life Sciences [q-bio], medicine.medical_treatment, Molecular Sequence Data, Lysine, Mutant, Organophosphonates, CHO Cells, Biology, Glutamyl Aminopeptidase, Aminopeptidases, Biochemistry, Catalysis, Substrate Specificity, Mice, Glutamates, Cricetinae, [CHIM] Chemical Sciences, medicine, [CHIM]Chemical Sciences, Animals, Humans, Histidine, Amino Acid Sequence, Sulfhydryl Compounds, Enzyme kinetics, Enzyme Inhibitors, chemistry.chemical_classification, Metalloproteinase, Protease, Dose-Response Relationship, Drug, Wild type, Recombinant Proteins, Rats, [SDV] Life Sciences [q-bio], Enzyme Activation, Enzyme, chemistry, Mutagenesis, Site-Directed, Calcium, Asparagine
Abstract

International audience; Aminopeptidase A (EC 3.4.11.7, APA) is a 130 kDa membrane-bound protease that contains the HEXXH consensus sequence found in the zinc metalloprotease family, the zincins. In addition to the catalytic zinc atom, APA contains a Ca2+ ion that increases its enzymatic activity. Aligning the sequences of the mouse APA, APN, and other monozinc aminopeptidases led to the identification of a conserved histidine (His 450 in mouse APA). Replacing this residue with a phenylalanine (Phe 450) by site-directed mutagenesis resulted in markedly lower levels of APA activity and in a change in the sensitivity of APA to Ca2+ (the EC50 for Ca2+ was 25 microM in the wild type and only 279 microM in the mutant). Kinetic studies, with a supramaximal Ca2+ concentration (4 mM), showed that the Km of the mutant enzyme for the substrate alpha-L-glutamyl-beta-naphthylamide was 25 times higher than that of the wild type, whereas the kcat value was much lower (factor of 22). Thus, overall, the wild-type enzyme had a cleavage efficiency that was 571 times higher than that of the mutant. The inhibitory potencies of two different classes of inhibitors, a glutamate thiol and a glutamate phosphonate compound, were significantly lower (factors of 19 and 22, respectively) for the mutated enzyme than for the wild-type enzyme. In contrast, inhibition by lysine thiol was unaffected. These data strongly suggest that His 450 is critical for catalytic activity and is involved in substrate binding via interaction with the P1 carboxylate side chain of the substrate. Furthermore, His 450, together with Ca2+, may contribute to the substrate specificity of APA for N-terminal acidic amino acid residues.

Published
2000
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43. Investigation of Subsite Preferences in Aminopeptidase A (EC 3.4.11.7) Led to the Design of the First Highly Potent and Selective Inhibitors of This Enzyme

Author

Nadia De Mota, Marie-Claude Fournie-Zaluski, Bernard P. Roques, Sophie Danascimento, Aurélie Mothé, Christelle David, Hervé Meudal, Laurent Bischoff, Catherine Llorens-Cortes, Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bischoff, Laurent, Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Magnetic Resonance Spectroscopy, Swine, [SDV]Life Sciences [q-bio], [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Tripeptide, Aminopeptidases, 01 natural sciences, chemistry.chemical_compound, [CHIM] Chemical Sciences, Drug Discovery, Aspartic acid, Peptide synthesis, Enzyme Inhibitors, chemistry.chemical_classification, Molecular Structure, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.CATA] Chemical Sciences/Catalysis, Stereoisomerism, [CHIM.MATE]Chemical Sciences/Material chemistry, Recombinant Proteins, Biochemistry, Enzyme inhibitor, Molecular Medicine, Neprilysin, Rabbits, [CHIM.RADIO]Chemical Sciences/Radiochemistry, [CHIM.INOR] Chemical Sciences/Inorganic chemistry, Stereochemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, CD13 Antigens, Peptidyl-Dipeptidase A, Glutamyl Aminopeptidase, 010402 general chemistry, [CHIM.RADIO] Chemical Sciences/Radiochemistry, [CHIM]Chemical Sciences, Animals, [CHIM.MATE] Chemical Sciences/Material chemistry, 010405 organic chemistry, Active site, [CHIM.CATA]Chemical Sciences/Catalysis, [CHIM.ORGA] Chemical Sciences/Organic chemistry, Angiotensin II, Rats, 0104 chemical sciences, Enzyme, chemistry, Glutamyl aminopeptidase, biology.protein
Abstract

The study of the physiological roles of the membrane-bound zinc-aminopeptidase A (glutamyl aminopeptidase, EC 3.4.11.7) needs the design of efficient and selective inhibitors of this enzyme. An acute exploration of aminopeptidase A active site was performed by a combinatorial approach using (3-amino-2-mercapto-acyl)dipeptides able to fit its S(1), S(1)', and S(2)' subsites. This analysis confirmed that the S(1) subsite is optimally blocked by a glutamate or isosteric residues and demonstrated that the S(1)' subsite is hydrophobic whereas the S(2)' subsite recognizes preferentially negatively charged residues derived from aspartic acid. The optimization of these structural parameters led to the synthesis of nanomolar and subnanomolar inhibitors of aminopeptidase A such as H(3)N(+)CH(CH(2)CH(2)SO(3)(-))CH(SH)CO-Ile-(3-COOH)Pro that exhibits a K(i) of 0.87 nM. The best compounds were synthesized by a stereochemically controlled route. These first described highly potent inhibitors could allow studies about the role of physiological substrates of APA such as angiotensin II and cholecystokinin CCK(8) in the central nervous system.

Published
1999
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44. Enhancement of Adenovirus-Mediated Gene Delivery by Use of an Oligopeptide with Dual Binding Specificity

Author

Ariane Galaup, Régis Peytavi, Pierre Boulanger, Nathalie Chazal, Saw See Hong, Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), AMMI Lab, Universty of Alberta, and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV]Life Sciences [q-bio], Transgene, Genetic Vectors, Molecular Sequence Data, Peptide, Gene delivery, Biology, medicine.disease_cause, Adenoviridae, Substrate Specificity, Mice, 03 medical and health sciences, 0302 clinical medicine, Gastrin-releasing peptide, Genetics, medicine, Animals, Humans, Amino Acid Sequence, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Oligopeptide, Binding Sites, Histocompatibility Antigens Class I, Genetic transfer, Gene Transfer Techniques, 3T3 Cells, Molecular biology, 3. Good health, Receptors, Bombesin, chemistry, Cell culture, 030220 oncology & carcinogenesis, Receptors, Virus, Molecular Medicine, Bombesin, Peptides, hormones, hormone substitutes, and hormone antagonists, HeLa Cells
Abstract

The efficiency of human adenovirus serotype 5 (Ad5) transgene delivery was tested on several human and animal cell lines in vitro, by using a bimodular 35-mer oligopeptide carrying two peptide domains with different ligand specificities. One domain mimicked the fiber knob-binding region of the alpha2 domain of human MHC-1 molecules (MH20), and the other corresponded to the gastrin-releasing peptide (GRP). Two synthetic peptides with different configurations were analyzed in Ad-mediated gene transfer assays using Ad5Luc3 vector carrying the luciferase reporter gene. One peptide (GRP-MH20) had the GRP domain on the N-terminal side of MH20, while the other (MH20-GRP), the C-terminally amidified GRP, was on the C-terminal side of MH20. The GRP-MH20 peptide, but not MH20-GRP, was capable of enhancing luciferase gene delivery to Ad-susceptible cells in a GRP receptor-dependent manner. More importantly, GRP-MH20 could also confer susceptibility to Ad infection to normal or cancer cells that lack fiber receptors for the virus. Our data suggested that GRP receptors could function efficiently as alternative attachment receptors for Ad5, but that Ad5 bound to GRP receptors still depended, at least partially, on the penton base-mediated endocytotic pathway for subsequent cell entry. Gene delivery by a human adenovirus serotype 5 (Ad5) vector was assayed with a bimodular oligopeptide carrying two peptide domains of different binding specificities. One domain was a high-affinity peptide ligand of the Ad5 fiber knob (MH20), and the other corresponded to the gastrin-releasing peptide (GRP). The synthetic peptide GRP-MH20 was found to be capable of enhancing Ad-mediated gene transfer to Ad-susceptible cells in a GRP receptor-dependent manner. More importantly, GRP-MH20 could also confer susceptibility to Ad infection to normal or cancer cells that lack fiber receptors. Our data suggested that GRP receptors could function efficiently as alternative attachment receptors for Ad5, but virus bound to GRP receptors still depended partially on the penton base-mediated pathway for cell entry.

Published
1999
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45. A Novel Distal Enhancer Confers Chorionic Expression on the Human Renin Gene

Author

Fabrice Bonnet, Stéphane Germain, Josette Philippe, Florence Pinet, Sebastien Fuchs, Pierre Corvol, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Enhancer Elements, Cells, Molecular Sequence Data, Cell, Sequence Homology, Enhancer RNAs, Regulatory Sequences, Nucleic Acid, 030204 cardiovascular system & hematology, Biology, Biochemistry, Promoter Regions, 03 medical and health sciences, 0302 clinical medicine, Genetic, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Sequence Homology, Nucleic Acid, Renin, Renin–angiotensin system, medicine, Animals, Humans, Site-Directed, Binding site, Promoter Regions, Genetic, Enhancer, Molecular Biology, Gene, Transcription factor, Cells, Cultured, DNA Primers, 030304 developmental biology, Cell Nucleus, 0303 health sciences, Cultured, Base Sequence, Nucleic Acid, Promoter, Chorion, Cell Biology, Molecular biology, Enhancer Elements, Genetic, medicine.anatomical_structure, Mutagenesis, COS Cells, Mutagenesis, Site-Directed, Regulatory Sequences
Abstract

International audience; Renin catalyzes the rate-limiting step of the renin-angiotensin system, which regulates blood pressure and electrolyte homeostasis. To determine cell-specific human renin gene control elements, the transcriptional activity of promoter regions up to position -8876 was studied in renin-expressing cells. A positive regulatory region conferring approximately 57-fold higher transcriptional activity to the human renin gene promoter in chorionic cells was identified between nucleotides -5777 and -5552. It had the orientation-independent activity typical of classical enhancers. It also conferred approximately 59-fold higher transcriptional levels from the heterologous simian virus 40 (SV40) promoter in chorionic cells and approximately 6-fold higher transcriptional levels in Calu-6 and As4.1 cells, whereas no effect was measured in non-renin-expressing cells. DNase I footprinting showed that this enhancer contains three binding sites for chorionic cell nuclear extracts. Functional analysis suggested that the activity of the enhancer is regulated by differential mechanisms in the three renin-expressing cells involving a complex arrangement of AP-1 motifs binding cell-specific members of the basic leucine zipper family of transcription factors. Thus, our results demonstrate that this enhancer plays a key role in the expression of the human renin gene in the chorion and may also be involved in its regulated expression in other tissues.

Published
1998
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46. Immunocytochemical Localization of the Prohormone Convertases PC1 and PC2 in Rat Prolactin Cells

Author

Laurent Muller, R. Picart, C Tougard, Nabil G. Seidah, A. Barret, Müller, Laurent, Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Montréal (UdeM)

Subjects
Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, Histology, [SDV]Life Sciences [q-bio], Blotting, Western, Immunoblotting, Prohormone, Golgi Apparatus, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cytoplasmic Granules, Cell Line, Prolactin cell, 03 medical and health sciences, symbols.namesake, Anterior pituitary, Pituitary Gland, Anterior, Internal medicine, medicine, Animals, Aspartic Acid Endopeptidases, Subtilisins, Rats, Wistar, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, Neuroendocrine cell, Secretory pathway, 030102 biochemistry & molecular biology, Endoplasmic reticulum, Golgi apparatus, Subcellular localization, Immunohistochemistry, Prolactin, Rats, Cell biology, [SDV] Life Sciences [q-bio], Proprotein Convertase 2, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, symbols, Endoplasmic Reticulum, Rough, Proprotein Convertases, Anatomy, medicine.drug
Abstract

SUMMARY The prohormone convertases PC1 and PC2 are subtilisin-related endopeptidases that process prohormone and neuropeptide precursors. Using different ultrastructural immunocytochemical approaches, we have investigated their intracellular distribution in a neuroendocrine cell type that has not been examined thus far, the rat anterior pituitary lactotrope. These cells secrete mainly prolactin and also express the neuroendocrinespecific protein secretogranin II, which is considered a peptide precursor. Our study provides evidence for the expression of PC1 and PC2 in rat lactotropes and provides new information on their subcellular localization. Apart from their presence in the secretory granules, PC1 and PC2 displayed different major localization along the secretory pathway. PC1 immunoreactivity was concentrated in the Golgi apparatus, whereas PC2 immunoreactivity was prominent in the rough endoplasmic reticulum (RER). These observations provide morphological support for previous biochemical analysis of proPC1 and proPC2 post-translational processing, which has demonstrated that PC1 exits very rapidly from the RER, whereas PC2 is retained much longer in this compartment. (J Histochem Cytochem 46:101‐108, 1998)

Published
1998
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47. Accident vasculaire cérébral : Protection de l’intégrité vasculaire lors de la reperfusion

Author

Stéphane Germain, Thomas Mathivet, Catherine Monnot, Claire Bouleti, Bertrand Lapergue, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, business.industry, Medicine, General Medicine, business, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract

International audience

Published
2014
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48. Hypoxia and extracellular matrix remodeling

Author

Stéphane Germain, Laurent Muller, Catherine Monnot, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Jean-Jacques Feige, Gilles Pagès, Fabrice Soncin, École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Basement membrane, 0303 health sciences, Angiogenesis, Matricellular protein, Biology, Mural cell, Cell biology, Vascular endothelial growth factor, Extracellular matrix, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine.anatomical_structure, chemistry, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030220 oncology & carcinogenesis, medicine, Signal transduction, 030304 developmental biology, Blood vessel
Abstract

International audience; Hypoxia regulates composition of both the vascular basement membrane (BM) and the extracellular matrix (ECM) by modulating deposition, cross-linking, posttranslational modifications, and rearrangement events but also degradation. Hypoxia-driven remodeling of the ECM includes highly temporally and spatially coordinated processes that eventually affect angiogenesis leading to blood vessel formation from existing blood vessels. Hypoxia thereby affects the mechanical properties of the vascular milieu as well as matricellular proteins expression and function and availability of angiogenesis-regulating growth factors such as vascular endothelial growth factor (VEGF). ECM composition and stiffness may be required for optimal VEGFR2 expression and vascular development in vitro and in vivo (Mammoto et al. Nature 2009), but how it might control signaling pathways such as VEGFR2 signaling is not fully appreciated yet. Thus, vascular BM and ECM composition affects vascular microenvironment architecture and interaction with angiogenic growth factors but also exerts mechanical forces controlled by physical interactions between vascular cells and the ECM that cooperate in regulating angiogenesis.

Published
2014
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49. Restoration of connexin 40 (cx40) in Renin-producing cells reduces the hypertension of cx40 null mice

Author

Paolo Meda, Stéphane Germain, Jacques-Antoine Haefliger, Loïc Le Gal, Florian Alonso, Charlotte Wagner, Denise Nardelli Haefliger, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
medicine.medical_specialty, Afferent arterioles, Nitric Oxide Synthase Type III, Blotting, Western, Connexin, Blood Pressure, Mice, Transgenic, 030204 cardiovascular system & hematology, Biology, Kidney, Nitric Oxide, Connexins, Nitric oxide, Renin-Angiotensin System, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Enos, Internal medicine, Renin–angiotensin system, Renin, Internal Medicine, medicine, Myocyte, Animals, Humans, Promoter Regions, Genetic, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Endothelial Cells, biology.organism_classification, Immunohistochemistry, Receptor, TIE-2, Mice, Inbred C57BL, Platelet Endothelial Cell Adhesion Molecule-1, Arterioles, Blood pressure, medicine.anatomical_structure, Endocrinology, chemistry, Hypertension, Endothelium, Vascular
Abstract

Connexin 40 (Cx40) is expressed by the renin-producing cells (RSCs) of the kidneys and the endothelial cells of blood vessels. Cx40 null mice (Cx40 −/− ) feature a much increased renin synthesis and secretion, which results in chronic hypertension, and also display an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels and nitric oxide production. To discriminate the effect of Cx40 in renin secretion and vascular signaling, we targeted Cx40 to either the RSCs or the endothelial cells of Cx40 null mice. When compared with Cx40 −/− controls, the animals expressing Cx40 in RSCs were less hypertensive and featured reduced renin levels, still numerous RSCs outside the wall of the afferent arterioles. In contrast, mice expressing Cx40 in the endothelial cells were as hypertensive as Cx40 −/− mice, in spite of control levels of Cx37 and eNOS. Our data show that blood pressure is improved by restoration of Cx40 expression in RSCs but not in endothelial cells, stressing the prominent role of renin in the mouse hypertension linked to loss of Cx40.

Published
2014
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50. Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice

Author

Vincent Richard, Stéphane Germain, David Coquerel, Ariane Galaup, Antoine Ouvrard-Pascaud, Alexandre Gueret, Marie Besnier, Paul Mulder, Jean-Paul Henry, Christian Thuillez, Ebba Brakenhielm, Lionel Nicol, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), and Brakenhielm, Ebba

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Angiogenesis, Left, Myocardial Infarction, 030204 cardiovascular system & hematology, Fibroblast growth factor, Biochemistry, Receptor tyrosine kinase, Ventricular Dysfunction, Left, Mice, 0302 clinical medicine, Cell Movement, Diastole, Smooth Muscle, Ventricular Dysfunction, Molecular Targeted Therapy, Non-Receptor Type 1, Cells, Cultured, Aorta, Inbred BALB C, Mice, Knockout, Protein Tyrosine Phosphatase, Non-Receptor Type 1, 0303 health sciences, Mice, Inbred BALB C, Cultured, Ventricular Remodeling, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Arterioles, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA Interference, Perfusion, Cell Division, Biotechnology, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction, medicine.medical_specialty, Cardiotonic Agents, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cells, Knockout, Myocytes, Smooth Muscle, Neovascularization, Physiologic, Biology, 03 medical and health sciences, Coronary circulation, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Coronary Circulation, growth factors, Genetics, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Ventricular remodeling, Physiologic, Molecular Biology, Neovascularization, 030304 developmental biology, Heart Failure, Myocytes, Endothelial Cells, Kinase insert domain receptor, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, cytokines, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Capillaries, Rats, Endocrinology, biology.protein, Protein Tyrosine Phosphatase, vascular growth
Abstract

International audience; The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ven-tricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B ؊/؊ mice [؉7؎2% vs. wild-type (WT), P ‫؍‬ 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissocia-tion of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macro-phages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF-induced migration and proliferation of mouse heart microvascular endo-thelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B ؊/؊ mice, increased LV capillary density (؉21؎3% vs. WT; P

Published
2014
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