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27 results on '"Laboratoire de développement et vieillissement de l'endothélium"'

1. Soluble vascular endothelial (VE) cadherin and autoantibodies to VE-cadherin in rheumatoid arthritis patients treated with etanercept or adalimumab

Author

Xavier Le-Loët, Christopher Banse, Estelle Houivet, Christian Marcelli, Barry Stidder, Helena Polena, Isabelle Vilgrain, Olivier Vittecoq, Peggy Philippe, Patrice Fardellone, Thierry Lequerré, Abir Khalil-Mgharbel, CHU Rouen, Normandie Université (NU), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Systèmes Nanobiotechnologiques et Biomimétiques (TIMC-IMAG-SyNaBi), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Service de rhumatologie, CHU Amiens-Picardie, Service de Rhumatologie [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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), and Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Systemic disease, Soluble VE cadherin, Severity of Illness Index, Gastroenterology, Etanercept, Arthritis, Rheumatoid, Cohort Studies, 0302 clinical medicine, Longitudinal Studies, Prospective Studies, skin and connective tissue diseases, Middle Aged, Cadherins, Treatment Outcome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Biomarker (medicine), Female, France, medicine.drug, Adult, musculoskeletal diseases, medicine.medical_specialty, Anti-vascular endothelial-cadherin antibody, Risk Assessment, 03 medical and health sciences, Rheumatology, Antigens, CD, Internal medicine, medicine, Adalimumab, Humans, Rheumatoid factor, Aged, Autoantibodies, 030203 arthritis & rheumatology, business.industry, Autoantibody, medicine.disease, 030104 developmental biology, Solubility, Immunology, Methotrexate, business, Biomarkers, Follow-Up Studies
Abstract

Objectives The aim of this study was to investigate the clinical value of sVE and anti-vascular endothelial-cadherin antibodies (AAVE) in RA treated with etanercept or adalimumab combined with methotrexate. Methods This was an 18-month prospective multicenter study in which patients had active RA, requiring TNF antagonist. sVE rates and AAVE titers were measured respectively by dot blot and ELISA. The relationship of these biomarkers with parameters reflecting articular or systemic disease activity, progression of structural damage, and response or remission to treatment was analyzed. Results Forty-eight patients received TNF blocking agents. Variation of sVE rates were significantly correlated with that of C-reactive protein (CRP) levels at weeks 6, 12, 26 and 52. A significant decrease in sVE levels was observed in the group of patients exhibiting a decrease in CRP levels as compared to the patient group with unmodified CRP. AAVE at baseline were correlated with rheumatoid factor. Kinetics analysis of sVE levels and AAVE titers showed that their level were not associated with disease activity score and to methotrexate/adalimumab or etanercept response. Conclusions sVE is a biomarker associated with systemic RA activity under anti-TNF. AAVE are related to autoantibodies usually associated to RA.

Published
2017
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2. A Biomimetic Lipid Membrane Device Reveals the Interaction of Cancer Biomarkers with Human Serum Lipidic Moieties

Author

Abir Khalil-Mgharbel, Paul K. Dembélé, Isabelle Vilgrain, Jean-Pierre Alcaraz, Md. Mehadi Hasan Sohag, Donald K. Martin, Helena Polena, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Systèmes Nanobiotechnologiques et Biomimétiques (TIMC-IMAG-SyNaBi), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), and Alcaraz, Jean-Pierre

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Lipoproteins, [SPI.NANO] Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, [SDV]Life Sciences [q-bio], Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Applied Microbiology and Biotechnology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Biomimetic Materials, Biomarkers, Tumor, medicine, Humans, Immunoprecipitation, Nanotechnology, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, education, Lipid bilayer, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Apolipoprotein A-I, biology, Chemistry, Cancer, General Medicine, Models, Theoretical, Cadherins, medicine.disease, Kidney Neoplasms, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, [SDV] Life Sciences [q-bio], Cholesterol, HEK293 Cells, 030104 developmental biology, Biochemistry, 030220 oncology & carcinogenesis, biology.protein, Molecular Medicine, Biomarker (medicine), lipids (amino acids, peptides, and proteins), Apolipoprotein A1, Cancer biomarkers, Ultracentrifuge, Biotechnology, Lipoprotein
Abstract

A major problem for the detection of cancer biomarkers in plasma or serum is that common clinical practice does not require the patient to be in a fasting state. Considering that lipoproteins are the main population affected by food intake, the authors hypothesized that biomarkers could be embedded in lipid particles and thereby opens a new avenue for detection. Using the recently published biomarker, soluble VE-cadherin (sVE), the authors tested our hypothesis using techniques of biophysics, biochemistry and the tools of nanobiotechnology on serum samples from kidney cancer patients (n = 106). Optical density as well as contact angle measurements of serum revealed heterogeneity in the particle content of the serum samples. Isolation of the lipidic moieties by ultracentrifugation showed that sVE was detected in this compartment. Further, isolation of lipoprotein subclasses by precipitation with sodium phosphotungstate and MgCl2 , showed that HDL carried the majority of sVE. Immunoprecipitation of sVE confirmed that it was associated with Apolipoprotein A1, a major compound of HDL. Using a biomimetic lipid bilayer membrane coupled with impedance spectroscopy the authors quantified, in real-time, that the sVE adsorbed to the lipid bilayer membrane without altering its structure. Taken together, these results show for the first time a direct interaction of a cancer biomarker with lipids. The authors anticipate these results to prompt fasting for future blood tests for large-scale studies in the biomarkers research field.

Published
2018

3. Soluble VE-cadherin in metastatic breast cancer: an independent prognostic factor for both progression-free survival and overall survival

Author

Helena Polena, Thomas Bachelot, Olivier Tredan, Isabelle Vilgrain, François-Clément Bidard, Jean-Yves Pierga, Camille Schiffler, Abir Khalil-Mgharbel, Etienne Brain, Sylvie Chabaud, Pauline Rochefort, Centre Léon Bérard [Lyon], Service d'Oncologie Médicale, Institut Curie [Paris], Institut Curie - Saint Cloud (ICSC), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogénèse et progression tumorale, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Saint-Cloud], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
0301 basic medicine, Oncology, Adult, Cancer Research, Prognostic variable, medicine.medical_specialty, Colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, survival, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Antigens, CD, Internal medicine, medicine, Biomarkers, Tumor, Humans, Progression-free survival, Neoplasm Metastasis, skin and connective tissue diseases, Lung cancer, prognostic factor, Molecular Diagnostics, Survival analysis, Aged, Aged, 80 and over, business.industry, soluble VE-cadherin, Middle Aged, medicine.disease, Cadherins, Prognosis, Metastatic breast cancer, Survival Analysis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Disease Progression, Female, metastatic breast cancer, business, Liver cancer
Abstract

Background: Patients with metastatic breast cancer (MBC) represent a heterogeneous group, with large differences in outcomes from individual patients. VE-cadherin, an endothelial-specific cadherin, was shown to promote tumour proliferation and angiogenesis. Soluble VE-cadherin has been recently associated to breast cancer progression. This study was designed to investigate the prognosis significance of soluble VE-cadherin in hormone-refractory MBC. Methods: Between 2004 and 2007, 150 patients with a fully documented history of hormone-refractory MBC were included in the prospective SEMTOF study. Serum concentrations of VE-cadherin were measured at inclusion for 141 patients and 6 weeks after the beginning of chemotherapy, using a sandwich enzyme immunoassay. Results: The presence of high levels of serum VE-cadherin was significantly correlated to a shorter progression-free (PFS) and overall survival (OS). In a multivariate analysis along with clinical and biologic prognostic parameters, high serum VE-cadherin level was an independent adverse prognostic variable for PFS (median PFS 9.7 (IC95: 8; 11.9) vs 5.8 (IC95: 4.1; 8) months P=0.0008) and OS (median OS 34 (IC95: 26.6; 47.1) vs 14.8 (IC95: 9.3; 21.4) months P=0.0007). Moreover, VE-cadherin decrease during chemotherapy was also associated with good prognosis. Conclusions: Serum VE-cadherin levels correlate to poorer survival in patients with hormone-refractory MBC. As sVE-cadherin reflects tumour angiogenesis, this could have therapeutic implications for antiangiogenic treatment.

Published
2016
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4. Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein

Author

Emmanuelle Tillet, Anne-Sophie Gauchez, Francine Cand, Stéphanie Bouillot, Marie-Hélène Prandini, Philippe Huber, Pascale Hoffmann, Nadia Alfaidy, Guillaume Carmona, Alfaidy, Nadia, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), 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), 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)-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), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme de radioactivité [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)

Subjects
0303 health sciences, Cadherin, ADAM10, Protocadherin, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Biology, Biochemistry, Molecular biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Downregulation and upregulation, Cell–cell interaction, medicine, Signal transduction, Cell adhesion, Molecular Biology, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

International audience; Protocadherins are a group of transmembrane proteins with homophilic binding activity, members of the cadherin superfamily. Apart from their role in adhesion, the cellular functions of protocadherins are essentially unknown. Protocadherin (PCDH)12 was previously identified in invasive trophoblasts and endothelial and mesangial cells in the mouse. Invalidation studies revealed that the protein was required for optimal placental development. In this article, we show that its human homolog is abundantly expressed in various trophoblast subtypes of the human placenta and at lower levels in endothelial cells. We demonstrate that PCDH12 is shed at high rates in vitro. The shedding mechanism depends on ADAM10 and results in reduced cellular adhesion in a cell migration assay. PCDH12 is subsequently cleaved by the γ-secretase complex, and its cytoplasmic domain is rapidly degraded by the proteasome. PCDH12 shedding is regulated by interlinked intracellular pathways, including those involving protein kinase C, PI3K, and cAMP, that either increase or inhibit cleavage. In endothelial cells, VEGF, prostaglandin E(2), or histamine regulates PCDH12 shedding. The extracellular domain of PCDH12 was also detected in human serum and urine, thus providing evidence of PCDH12 shedding in vivo. Importantly, we observed an increase in circulating PCDH12 in pregnant women who later developed a pre-eclampsia, a frequent pregnancy syndrome and a major cause of maternal and fetal morbidity and mortality. In conclusion, we speculate that, like in mice, PCDH12 may play an important role in human placental development and that proteolytic cleavage in response to external factors, such as cytokines and pathological settings, regulates its activity.

Published
2011
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5. Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth

Author

Jean-Christophe Deloulme, Sylvie Gory-Fauré, Franck Mauconduit, Sophie Chauvet, Julie Jonckheere, Benoit Boulan, Erik Mire, Jing Xue, Marion Jany, Caroline Maucler, Agathe Deparis, Olivier Montigon, Alexia Daoust, Barbier, Emmanuel L., Christophe Bosc, Nicole Déglon, Jacques Brocard, Eric Denarier, Isabelle Le Brun, Karin Pernet-Gallay, Isabelle Vilgrain, Phillip Robinson, Hana Lahrech, Fanny Mann, Annie Andrieux, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Neurosciences, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), 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), State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, Centre de recherche en neurosciences de Lyon (CRNL), 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), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Physiopathologie du Cytosquelette, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), 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 Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratory of Developmental Biology, McGill University = Université McGill [Montréal, Canada], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire de développement et vieillissement de l'endothélium, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Inserm U836, équipe 7, Nanomédecine et cerveau, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), The University of Sydney, Lausanne University Hospital, Lausanne university hospital, INSERM, CEA, Univ. Grenoble Alpes, National Health and Medical Research Council of Australia, ANR-10-BLAN-1202,CBioS,Fonctions cellulaires des protéines STOP : vers une compréhension fonctionnelle et moléculaire du rôle des microtubules dans la transmission synaptique et l'organisation neuronale(2010), and ANR-11-INBS-0006,FLI,France Life Imaging(2011)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Fornix, Brain, Semaphorins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microtubules, Article, src Homology Domains, Animals, Axons/metabolism, Brain/metabolism, Brain/pathology, Diffusion Tensor Imaging, Fornix, Brain/embryology, Fornix, Brain/metabolism, Glycoproteins/metabolism, HEK293 Cells, Humans, Magnetic Resonance Imaging, Membrane Proteins/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Microtubule-Associated Proteins/genetics, Neural Pathways/embryology, Neural Pathways/metabolism, Neurites/metabolism, Neuroanatomical Tract-Tracing Techniques, Neurons/metabolism, Organ Size, Neural Pathways, Neurites, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Glycoproteins, Neurons, Brain, Membrane Proteins, Development of the nervous system, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Axons, Cytoskeletal proteins, nervous system, Microtubule-Associated Proteins, Cell signalling
Abstract

Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post-commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts., Loss of the structural microtubule-associated protein 6 (MAP6) leads to neuronal differentiation defects that are independent of MAP6's microtubule-binding properties. Here the authors establish a functional link between MAP6 and Semaphorin 3E signalling for proper formation of the fornix of the brain.

Published
2015
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6. BIOBRAD Study: The Search for Biomarkers of Bradykinin-Mediated Angio-Oedema Attacks

Author

Maxime Maignan, Chantal Dumestre-Pérard, Abir Khalil-Mgharbel, Marie-Cécile Fevre, Alban Deroux, Laurence Bouillet, Isabelle Vilgrain, Isabelle Boccon-Gibod, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), 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]), Institut méditerranéen de biodiversité et d'écologie marine et continentale (IMBE), Avignon Université (AU)-Aix Marseille Université (AMU)-Institut de recherche pour le développement [IRD] : UMR237-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UMR237-Aix Marseille Université (AMU)-Avignon Université (AU)

Subjects
Adult, Male, Time Factors, Immunology, Bradykinin, Angio-oedema, Fibrin Fibrinogen Degradation Products, 030207 dermatology & venereal diseases, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Antigens, CD, Immunology and Allergy, Medicine, Humans, Prospective Studies, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Angioedema, Aged, Aged, 80 and over, business.industry, General Medicine, Complement System Proteins, Middle Aged, ANTIGENS CD, Cadherins, Emergency situations, 3. Good health, 030228 respiratory system, chemistry, Female, medicine.symptom, business, Complement C1 Inhibitor Protein, Biomarkers
Abstract

The aetiology of angio-oedema (AE) is difficult to determine; however, it is essential in emergency situations when two major contexts may be present: mast cell-mediated AE and bradykinin-mediated AE. Different forms of AE are currently distinguished based on clinical criteria (spontaneous duration of the attack, presence of concomitant or late-appearing superficial urticaria, history of atopy, and others), but specific biomarkers could improve patient management.In this prospective study, potential biomarkers have been identified, and their statistical characteristics were examined.Samples were taken on day 0 (D0) and D7 for 3 patient groups (n = 11 each): bradykinin-mediated AE [peripheral site of attack, ear, nose, throat (ENT), and abdominal involvement], mast cell-mediated AE, and non-bradykinin-mediated abdominal pain.Assay of the potential biomarkers revealed no significant differences in C1 inhibitor and C4 levels. In contrast, D-dimer levels peaked during bradykinin-mediated AE attacks (median 2.2 mg/l at D0 vs. 0.52 mg/l at D7; p10-3) as well as during mast cell-mediated AE attacks (1.97 vs. 0.65 mg/l; p = 0.04) and were high in bradykinin-mediated AE compared to the control group (0.69 mg/l; p = 0.01). A threshold value of 0.62 mg/l was found to have a negative predictive value of 100% for bradykinin-mediated AE compared to other causes of abdominal pain (group 3). Circulating VE-cadherin levels were also increased during an attack (1,990 at D0 vs. 1,566 ng/ml at D7; p = 0.01), but could not distinguish between bradykinin-mediated and mast cell-mediated AE, like D-dimers.Exploration of changes in fibrinolysis-related markers (particularly D-dimers) is thus promising for the diagnosis of AE attacks in difficult-to-diagnose abdominal forms, although it was not able to differentiate between bradykinin and mast cell-mediated AE.

Published
2015
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7. Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction

Author

Helena Polena, Isabelle Vilgrain, Sophie Blaise, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hypoxie et physiopathologies cardiovasculaire et respiratoire, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pathology, medicine.medical_specialty, Molecular Sequence Data, Inflammation, autoimmune disease, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, endothelial dysfunction, Autoimmune Diseases, Adherens junction, Capillary Permeability, sepsis, Antigens, CD, Predictive Value of Tests, Medicine, Animals, Humans, cancer, Amino Acid Sequence, Vascular Diseases, Endothelial dysfunction, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Autoantibodies, business.industry, Autoantibody, biomarkers, medicine.disease, Cadherins, Prognosis, Transmembrane protein, 3. Good health, Vascular endothelial growth factor B, Vascular endothelial growth factor A, Vascular endothelial growth factor C, inflammation, Cancer research, Endothelium, Vascular, medicine.symptom, atherosclerosis, Cardiology and Cardiovascular Medicine, business
Abstract

International audience; Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokine-induced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein - soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases.

Published
2015
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8. Angiogenesis: The VE-Cadherin Switch

Author

Philippe Huber, Isabelle Vilgrain, Yann Wallez, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Huber, Philippe

Subjects
Angiogenesis, MESH: Cell Cycle, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Protein tyrosine phosphatase, Biology, Vascular endothelial growth inhibitor, MESH: Cadherins, MESH: Atherosclerosis, MESH: Tyrosine, Capillary Permeability, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Neoplasms, Humans, MESH: Endothelial Cells, MESH: Neoplasms, Phosphorylation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Antigens, CD, 030304 developmental biology, 0303 health sciences, MESH: Humans, Neovascularization, Pathologic, MESH: Phosphorylation, MESH: Vascular Endothelial Growth Factor Receptor-2, Cell Cycle, MESH: Capillary Permeability, Endothelial Cells, Atherosclerosis, Cadherins, Vascular Endothelial Growth Factor Receptor-2, MESH: Gene Expression Regulation, FLT4, Cell biology, Vascular endothelial growth factor A, Gene Expression Regulation, Vascular endothelial growth factor C, 030220 oncology & carcinogenesis, Cancer research, Tyrosine, Endothelium, Vascular, MESH: Endothelium, Vascular, VE-cadherin, MESH: Neovascularization, Pathologic, Cardiology and Cardiovascular Medicine
Abstract

International audience; Because angiogenesis is a key step in a number of pathologic processes, including tumor growth and atherosclerosis, many research studies have investigated the regulatory signals active at various stages of vascular invasion. The differential activities of the endothelial junction protein vascular endothelial (VE)-cadherin reflect the versatile behavior of endothelial cells between vascular quiescence and angiogenesis. VE-cadherin function and signaling are deeply modified in proliferating cells, and this conversion is accompanied by phosphorylation of the protein on tyrosine residues and enhanced transcription of its gene. Recent advances in the complex interplay between protein tyrosine kinases and phosphatases regulating VE-cadherin phosphorylation and function are discussed in this review.

Published
2006
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9. Towards a specific marker for acute bradykinin-mediated angioedema attacks: a literature review

Author

Alban Deroux, Chantal Dumestre-Pérard, Laurence Bouillet, Isabelle Vilgrain, Isabelle Boccon-Gibod, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Centre Hospitalier Universitaire [Grenoble] (CHU), Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Bradykinin, Dermatology, Disease, endothelial dysfunction, C1-inhibitor, Fibrin Fibrinogen Degradation Products, chemistry.chemical_compound, Von Willebrand factor, medicine, Humans, Mast Cells, Angioedema, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, vascular permeability, VE cadherin, C1 inhibitor, Endothelin-1, biology, business.industry, Interleukins, biomarkers, Angiotensin-converting enzyme, medicine.disease, Blood Coagulation Factors, hereditary angioedema, 3. Good health, C-Reactive Protein, chemistry, Hereditary angioedema, Immunology, biology.protein, Biomarker (medicine), medicine.symptom, E-Selectin, business, Complement C1 Inhibitor Protein, Histamine
Abstract

Background: Bradykinin-mediated angioedema (AE) is a rare disease characterised by recurrent angioedema linked to acquired (e.g. angiotensin converting enzyme inhibitor induced AE) or hereditary disorders (e.g. AE type I or II). As the clinical picture can be misleading, diagnosis of this disease is sometimes difficult. A bradykinin-mediated AE attack may be a therapeutic emergency which requires access to effective, but expensive, treatments. Their prescription must therefore be justified. No specific marker of acute bradykinin-mediated AE attacks has yet been identified to facilitate the therapeutic decision but it has been sought in many studies. Purpose: This article reviews the literature on this type of biomarker, comparing candidate bradykinin-mediated AE markers to candidate markers of mast cell activation. Conclusion: The most interesting biomarkers are those linked to endothelial stress (VE cadherin, E-selectin, endothelin-1, von Willebrand factor and its activity) which is significantly increased during an AE attack. All these markers must now be validated by prospective studies to determine their specificity and utility in diagnosis.

Published
2015
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10. Hereditary angioedema: Key role for kallikrein and bradykinin in vascular endothelial-cadherin cleavage and edema formation

Author

Mélanie Arboleas, Mariela Subileau, Tiphaine Mannic, Isabelle Vilgrain, Christian Drouet, C. Massot, Philippe Huber, Laurence Bouillet, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Physiopathologie vasculaire : interactions cellulaires, signalisation et vieillissement, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), 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), 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)-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), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Médecine Interne, CHU Grenoble, Groupe de Recherche et d’Étude du Processus Inflammatoire (GREPI), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse bactérienne et réponses cellulaires (PBRC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de développement et vieillissement de l'endothélium, GREPI, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Adult, medicine.medical_specialty, Blotting, Western, Immunology, Bradykinin, Neuropeptide, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Peptide hormone, Cleavage (embryo), Capillary Permeability, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antigens, CD, Internal medicine, Edema, Humans, Immunology and Allergy, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Angioedemas, Hereditary, Kallikrein, Middle Aged, Cadherins, medicine.disease, 3. Good health, Endocrinology, medicine.anatomical_structure, 030228 respiratory system, chemistry, Hereditary angioedema, Circulatory system, Female, Kallikreins, business, Biomarkers, Blood vessel
Abstract

International audience

Published
2011
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11. Dynamic phosphorylation of VE-cadherin Y685 throughout mouse estrous cycle in ovary and uterus

Author

Soumalamaya Bama, Isabelle Vilgrain, Adama Sidibé, Laurence Bouillet, Helena Polena, Tiphaine Mannic, Nicolas Chaumontel, Philippe Huber, Danielle Gulino-Debrac, Jeremy Razanajatovo, Irene Marechal, Université Grenoble Alpes - Institut d'Administration des Entreprises (UGA IAE), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie vasculaire : interactions cellulaires, signalisation et vieillissement, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Time Factors, Gonadotropins, Equine, Physiology, Angiogenesis, [SDV]Life Sciences [q-bio], Chorionic Gonadotropin, chemistry.chemical_compound, 0302 clinical medicine, Phosphorylation, reproductive and urinary physiology, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Cadherins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Vascular endothelial growth factor, src-Family Kinases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Cardiology and Cardiovascular Medicine, Tyrosine kinase, hormones, hormone substitutes, and hormone antagonists, Proto-oncogene tyrosine-protein kinase Src, endocrine system, medicine.medical_specialty, Estrous Cycle, Ovary, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Vascular Remodeling, Biology, 03 medical and health sciences, Antigens, CD, Physiology (medical), Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Estrous cycle, urogenital system, Uterus, Tyrosine phosphorylation, Mice, Inbred C57BL, Endocrinology, chemistry, Tyrosine, Reports
Abstract

We previously reported that vascular endothelial growth factor induced vascular endothelial (VE)-cadherin tyrosine phosphorylation at Y685 in a Src-dependent manner in vitro. Here, we studied the occurrence of Y685 phosphorylation in vivo in the female reproductive tract because it is a unique model of physiological vascular remodeling dependent on vascular endothelial growth factor. We first developed and characterized an anti-phospho-specific antibody against the site Y685 of VE-cadherin to monitor VE-cadherin phosphorylation along the four phases of mouse estrous cycle, termed proestrus, estrus, metestrus, and diestrus. A dynamic profile of tyrosine phosphorylated proteins was observed in both uterus and ovary throughout mouse estrous cycle, including kinase Src, which was found highly active at the estrus phase. The extent of tyrosine phosphorylated VE-cadherin was low at proestrus but strongly increased at estrus and returned to baseline at metestrus and diestrus, suggesting a potent hormonal regulation of this specific process. Indeed, C57Bl/6 female mice treatment with pregnant mare serum gonadotropin and human chorionic gonadotropin confirmed a significant increase in phosphoY685-VE-cadherin compared with that in untreated mice. These results demonstrate that VE-cadherin tyrosine phosphorylation at Y685 is a physiological and hormonally regulated process in female reproductive organs. In addition, this process was concomitant with the early steps of vascular remodeling taking place at estrus stage, suggesting that phosphoY685-VE-cadherin is a biomarker of endothelial cell activation in vivo.

Published
2014

12. VE-cadherin, a potential marker for endothelial cell activation during hereditary angioedema attacks

Author

Isabelle Vilgrain, Laurence Bouillet, Clinique de médecine interne, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire de développement et vieillissement de l'endothélium, and Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0303 health sciences, business.industry, [SDV]Life Sciences [q-bio], Immunology, medicine.disease, 3. Good health, Endothelial stem cell, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Hereditary angioedema, medicine, Immunology and Allergy, VE-cadherin, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology
Abstract

International audience

Published
2014
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13. Exploring the role of circulating VE-cadherin (VE-C) in metastatic colorectal adenocarcinoma (mCA) patients (pts) treated by bevacizumab (Bev)

Author

Pierre Guibert, Ellen Blanc, Christelle De La Fouchardiere, Isabelle Vilgrain, Matthieu Sarabi, Françoise Desseigne, Olfa Derbel-Miled, Pascal Artru, Sylvie Chabaud, Nadia Oussaid, Helena Polena, Centre Léon Bérard [Lyon], Délégation à la Recherche Clinique et à l'Innovation [Lyon] (DRCI), UNICANCER - Centre Léon Bérard Lyon (Rhône)-Centre de Lutte Contre le Cancer de Lyon et Rhône-Alpes, IRAMAT-Centre de recherche en physique appliquée à l’archéologie (IRAMAT-CRP2A), Institut de Recherches sur les Archéomatériaux (IRAMAT), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Montaigne-Université de Technologie de Belfort-Montbeliard (UTBM)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Montaigne-Université de Technologie de Belfort-Montbeliard (UTBM), Laboratoire de développement et vieillissement de l'endothélium, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Clinique Saint Jean, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon]-UNICANCER - Centre Léon Bérard Lyon (Rhône), and Université de Technologie de Belfort-Montbeliard (UTBM)-Université d'Orléans (UO)-Université Bordeaux Montaigne (UBM)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Université d'Orléans (UO)-Université Bordeaux Montaigne (UBM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Bevacizumab, Endothelium, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Tumor response, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, cardiovascular system, medicine, Cancer research, Colorectal adenocarcinoma, VE-cadherin, business, ComputingMilieux_MISCELLANEOUS, 030215 immunology, medicine.drug, Predictive biomarker
Abstract

e14614^ Background: No predictive biomarker of tumor response or resistance to Bev has been identified in mCA. VE-C is an endothelium-specific adhesion molecule of vital importance for endothelium ...

Published
2014
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14. BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain

Author

Sabine Bailly, Mariela Subileau, Marie Bidart, Sandrine Levet, Emmanuelle Tillet, Nicolas Ricard, Michel Samson, Christine Mallet, Jean-Jacques Feige, Laurent David, Biologie du Cancer et de l'Infection (BCI ), 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), 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), Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Male, medicine.medical_treatment, Endothelial cells, Endogeny, Smad Proteins, ALK1, Serine, MESH: Hepatocytes, Mice, 0302 clinical medicine, Growth Differentiation Factor 2, MESH: Animals, MESH: Serine Endopeptidases, Furin, Aorta, 0303 health sciences, MESH: Middle Aged, Kinase, Serine Endopeptidases, MESH: Aorta, Middle Aged, Ligand (biochemistry), 3. Good health, Cell biology, Growth Differentiation Factors, Cytokine, Blood, Biochemistry, Liver, MESH: Epithelial Cells, 030220 oncology & carcinogenesis, MESH: Proprotein Convertases, Molecular Medicine, Phosphorylation, Female, Proprotein Convertases, Adult, MESH: Rats, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, BMP9, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Animals, Humans, Rats, Wistar, MESH: Growth Differentiation Factor 2, Molecular Biology, MESH: Mice, 030304 developmental biology, Pharmacology, MESH: Humans, Epithelial Cells, MESH: Adult, MESH: Smad Proteins, Cell Biology, MESH: Rats, Wistar, MESH: Growth Differentiation Factors, MESH: Male, Rats, Bile Ducts, Intrahepatic, MESH: Bile Ducts, Intrahepatic, biology.protein, NIH 3T3 Cells, Hepatocytes, MESH: Female, Function (biology), MESH: NIH 3T3 Cells
Abstract

International audience; Bone Morphogenetic Protein 9 (BMP9) has been recently found to be the physiological ligand for the activin receptor-like kinase 1 (ALK1), and to be a major circulating vascular quiescence factor. Moreover, a soluble chimeric ALK1 protein (ALK1-Fc) has recently been developed and showed powerful anti-tumor growth and anti-angiogenic effects. However, not much is known concerning BMP9. This prompted us to investigate the human endogenous sources of this cytokine and to further characterize its circulating form(s) and its function. Analysis of BMP9 expression reveals that BMP9 is produced by hepatocytes and intrahepatic biliary epithelial cells. Gel filtration analysis combined with ELISA and biological assays demonstrate that BMP9 circulates in plasma (1) as an unprocessed inactive form that can be further activated by furin a serine endoprotease, and (2) as a mature and fully active form (composed of the mature form associated with its prodomain). Analysis of BMP9 circulating levels during mouse development demonstrates that BMP9 peaks during the first 3 weeks after birth and then decreases to 2 ng/mL in adulthood. We also show that circulating BMP9 physiologically induces a constitutive Smad1/5/8 phosphorylation in endothelial cells. Taken together, our results argue for the role of BMP9 as a hepatocyte-derived factor, circulating in inactive (40%) and active (60%) forms, the latter constantly activating endothelial cells to maintain them in a resting state.

Published
2012
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15. Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta

Author

Yves Vandenbrouck, Philippe Huber, Christine Rampon, Marie-Hélène Prandini, Francine Cand, Stéphanie Bouillot, Adriana Climescu-Haulica, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie vasculaire : interactions cellulaires, signalisation et vieillissement, Laboratoire Biologie-Informatique-Mathématique (LBIM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), 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), 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), and C. Rampon was supported by the Ligue contre le Cancer and the Fondation pour la Recherche Médicale. This work was supported by recurrent grants from the Institut National de la Santé et de la Recherche Médicale, the Commissariat à l'Energie Atomique and Grenoble University

Subjects
Physiology, Angiogenesis, Placenta, MESH: Organ Size, [SDV]Life Sciences [q-bio], MESH: Glycogen, MESH: Animals, Newborn, MESH: Cadherins, MESH: Decidua, Mice, angiogenesis, 0302 clinical medicine, MESH: Pregnancy, Cell Movement, Pregnancy, MESH: Reverse Transcriptase Polymerase Chain Reaction, Morphogenesis, MESH: Animals, 10. No inequality, MESH: Cell Movement, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Decidua, Organ Size, Cadherins, MESH: Placenta, Transmembrane protein, trophoblasts, medicine.anatomical_structure, gene profiling, Female, Glycogen, Protocadherin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, MESH: Cell Adhesion, 03 medical and health sciences, MESH: Gene Expression Profiling, Cell Adhesion, Genetics, medicine, Extracellular, Animals, Cell adhesion, MESH: Mice, 030304 developmental biology, Cadherin, Gene Expression Profiling, Molecular biology, Protocadherins, MESH: Morphogenesis, Animals, Newborn, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, 030217 neurology & neurosurgery, knockout mice
Abstract

Protocadherins are transmembrane proteins exhibiting homophilic adhesive activities through their extracellular domain. Protocadherin 12 ( Pcdh12) is expressed in angiogenic endothelial cells, mesangial cells of kidney glomeruli, and glycogen cells of the mouse placenta. To get insight into the role of this protein in vivo, we analyzed PCDH12-deficient mice and investigated their placental phenotype. The mice were alive and fertile; however, placental and embryonic sizes were reduced compared with wild-type mice. We observed defects in placental layer segregation and a decreased vascularization of the labyrinth associated with a reduction in cell density in this layer. To understand the molecular events responsible for the phenotypic alterations observed in Pcdh12−/− placentas, we analyzed the expression profile of embryonic day 12.5 mutant placentas compared with wild-type placentas, using pangenomic chips: 2,289 genes exhibited statistically significant changes in expressed levels due to loss of PCDH12. Functional grouping of modified genes was obtained by GoMiner software. Gene clusters that contained most of the differentially expressed genes were those involved in tissue morphogenesis and development, angiogenesis, cell-matrix adhesion and migration, immune response, and chromatin remodeling. Our data show that loss of PCDH12 leads to morphological alterations of the placenta and to notable changes in its gene expression profile. Specific genes emerging from the microarray screen support the biological modifications observed in PCDH12-deficient placentas.

Published
2008
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16. Tracing the glycogen cells with protocadherin 12 during mouse placenta development

Author

Philippe Huber, Christine Rampon, Emmanuelle Tillet, Stéphanie Bouillot, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Huber, Philippe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
MESH: Trophoblasts, MESH: Glycogen, MESH: Cadherins, MESH: Decidua, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Pregnancy, Cell Movement, Pregnancy, MESH: Placentation, Decidual cells, MESH: Animals, MESH: Cell Movement, reproductive and urinary physiology, 0303 health sciences, Glycogen, Decidua, Obstetrics and Gynecology, Cadherins, Cell biology, Trophoblasts, medicine.anatomical_structure, embryonic structures, Female, medicine.medical_specialty, Protocadherin, Mice, Inbred Strains, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Mice, Inbred Strains, MESH: Cell Adhesion, 03 medical and health sciences, Fetal membrane, Placenta, Internal medicine, medicine, Cell Adhesion, Animals, Cell Lineage, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Biological Markers, Trophoblast, MESH: Cell Lineage, Embryonic stem cell, Placentation, Protocadherins, Endocrinology, Reproductive Medicine, chemistry, MESH: Female, 030217 neurology & neurosurgery, Biomarkers, Developmental Biology
Abstract

International audience; Among the different trophoblast subtypes of the mouse placenta, the glycogen cells (GC) are one of the trophoblast subtypes that invade the decidua. We previously established that GC specifically expressed protocadherin 12 (PCDH12). In this paper, we investigated the origin of the PCDH12-positive cells and we characterized their fate in the maternal tissues. Our data indicate that they directly originate from the central part of the ectoplacental cone at embryonic day (E) 7.5. PCDH12-positive cells start to accumulate glycogen from E10.5 and the first migrating cells could be observed from this age. Unlike other placental and decidual cells, GC do not express P-cadherin, which may explain their migration properties in this organ. In the decidua, GC settle in the vicinity of the maternal vascular sinuses but do not incorporate in the endothelium. By the end of gestation (E17.5), most GC islets of the decidua enter into a lytic phase and form large lacunae. These lacunae, filled with glycogen, may provide a substantial source of energy at the end of gestation or during delivery. Our data suggest that spongiotrophoblasts and GC are two independent lineages and we bring insights into GC migration and fate.

Published
2006
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17. Platelet-activating factor increases VE-cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3'-kinase

Author

Dominique Stengel, Ewa Ninio, Isabelle Vilgrain, Hélène Hudry-Clergeon, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by INSERM (EMI 02-19 and U525), Commissariat à l'Energie Atomique, Direction des Sciences du Vivant/ Département Réponse Dynamique Cellulaire/ Association pour la Recherche contre le Cancer (ARC#5588), Fédération Nationale des Centres de Lutte contre le Cancer, Fondation pour la Recherche Médicale, and Ligue Nationale contre le Cancer., Huber, Philippe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
PtdIns3'- kinase, Endothelial cells, Fluorescent Antibody Technique, Protein tyrosine phosphatase, MESH: Receptors, G-Protein-Coupled, Biochemistry, adherens junction, Receptor tyrosine kinase, MESH: Cadherins, Receptors, G-Protein-Coupled, MESH: Tyrosine, MESH: Benzoquinones, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, angiogenesis, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Benzoquinones, MESH: Animals, MESH: Endothelial Cells, Enzyme Inhibitors, Phosphorylation, MESH: Fluorescent Antibody Technique, MESH: Antigens, CD, Immunosorbent Techniques, Mitogen-Activated Protein Kinase 1, 0303 health sciences, Mitogen-Activated Protein Kinase 3, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, Quinones, Heart, Adherens Junctions, Protein-Tyrosine Kinases, Tyrphostins, Cadherins, Cell biology, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Tyrosine kinase, MESH: Mitogen-Activated Protein Kinase 3, Platelet-derived growth factor receptor, Biotechnology, Proto-oncogene tyrosine-protein kinase Src, MESH: Mitogen-Activated Protein Kinase 1, platelet-activating factor, MESH: Enzyme Activation, Lactams, Macrocyclic, Platelet Membrane Glycoproteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Protein-Tyrosine Kinases, Article, MESH: Quinones, Cell Line, Adherens junction, 03 medical and health sciences, Antigens, CD, MESH: Intracellular Signaling Peptides and Proteins, Genetics, Animals, RNA, Messenger, Platelet Activating Factor, MESH: Tyrphostins, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, VE cadherin, MESH: Immunosorbent Techniques, 030304 developmental biology, MESH: RNA, Messenger, MESH: Platelet Activating Factor, MESH: Phosphorylation, Akt, MESH: Embryo, Mammalian, MESH: Platelet Membrane Glycoproteins, Tyrosine phosphorylation, MESH: Lactams, Macrocyclic, MESH: 1-Phosphatidylinositol 3-Kinase, Embryo, Mammalian, FLT4, MESH: Cell Line, Enzyme Activation, MESH: Heart, MESH: Adherens Junctions, chemistry, Rifabutin, biology.protein, Tyrosine
Abstract

International audience; Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in endothelial permeability. This study was designed to characterize PAF receptor (PAF-R) expression and its specific contribution to the modifications of adherens junctions in mouse endothelial cells. We demonstrated that PAF-R was expressed in mouse endothelial cells and was functionally active in stimulating p42/p44 MAPK and phosphatidylinositol 3-kinase (PtdIns3'-kinase)/Akt activities. Treatment of cells with PAF induced a rapid time- and dose-dependent (10(-7) to 10(-10) M) increase in tyrosine phosphorylation of a subset of proteins ranging from 90 to 220 kDa, including the VE-cadherin, the latter effect being prevented by the tyrosine kinase inhibitors herbimycin A and bis-tyrphostin. We demonstrated that PAF promoted formation of multimeric aggregates of VE-cadherin with PtdIns3'-kinase, which was also inhibited by herbimycin and bis-tyrphostin. Finally, we show by immunostaining of endothelial cells VE-cadherin that PAF dissociated adherens junctions. The present data provide the first evidence that treatment of endothelial cells with PAF promoted activation of tyrosine kinases and the VE-cadherin tyrosine phosphorylation and PtdIns3'-kinase association, which ultimately lead to the dissociation of adherens junctions. Physical association between PtdIns3'-kinase, serving as a docking protein, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of PAF-induced cellular activation.

Published
2005
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18. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues.: VE-cadherin tyrosine phosphorylation

Author

Francine Cand, Isabelle Vilgrain, Danielle Gulino-Debrac, Yann Wallez, Nathalie Lambeng, Philippe Huber, Christine Rampon, Georges Christe, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), 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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cell Extracts, Umbilical Veins, Physiology, Angiogenesis, Gonadotropins, Equine, MESH: Cadherins, chemistry.chemical_compound, Mice, angiogenesis, 0302 clinical medicine, VE-cadherin, MESH: Cell Extracts, MESH: Animals, MESH: Proteins, MESH: Endothelial Cells, Tyrosine, Phosphorylation, 0303 health sciences, tyrosine kinase, Cadherins, Cell biology, 030220 oncology & carcinogenesis, MESH: Uterus, Female, MESH: Endothelium, Vascular, Cardiology and Cardiovascular Medicine, Tyrosine kinase, MESH: Neovascularization, Physiologic, Proto-oncogene tyrosine-protein kinase Src, MESH: Phosphotyrosine, MESH: Ovary, medicine.medical_specialty, endothelium, Proto-Oncogene Proteins pp60(c-src), Neovascularization, Physiologic, MESH: Umbilical Veins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, Cell Line, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Gonadotropins, Equine, Internal medicine, medicine, Animals, Humans, Phosphotyrosine, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Phosphorylation, MESH: Vascular Endothelial Growth Factor Receptor-2, Ovary, Uterus, Endothelial Cells, Proteins, Kinase insert domain receptor, Tyrosine phosphorylation, MESH: Proto-Oncogene Proteins pp60(c-src), Vascular Endothelial Growth Factor Receptor-2, MESH: Cell Line, Mice, Inbred C57BL, Endocrinology, chemistry, MESH: Vanadates, Endothelium, Vascular, Vanadates, MESH: Female
Abstract

International audience; Vascular endothelial-cadherin (VE-cadherin) plays a key role in angiogenesis and in vascular permeability. The regulation of its biological activity may be a central mechanism in normal or pathological angiogenesis. VE-cadherin has been shown to be phosphorylated on tyrosine in vitro under various conditions, including stimulation by VEGF. In the present study, we addressed the question of the existence of a tyrosine phosphorylated form of VE-cadherin in vivo, in correlation with the quiescent versus angiogenic state of adult tissues. Phosphorylated VE-cadherin was detected in mouse lung, uterus, and ovary but not in other tissues unless mice were injected with peroxovanadate to block protein phosphatases. Remarkably, VE-cadherin tyrosine phosphorylation was dramatically increased in uterus and ovary, and not in other organs, during PMSG/hCG-induced angiogenesis. In parallel, we observed an increased association of VE-cadherin with Flk1 (VEGF receptor 2) during hormonal angiogenesis. Additionally, Src kinase was constitutively associated with VE-cadherin in both quiescent and angiogenic tissues and increased phosphorylation of VE-cadherin-associated Src was detected in uterus and ovary after hormonal treatment. Src-VE-cadherin association was detected in cultured endothelial cells, independent of VE-cadherin phosphorylation state and Src activation level. In this model, Src inhibition impaired VEGF-induced VE-cadherin phosphorylation, indicating that VE-cadherin phosphorylation was dependent on Src activation. We conclude that VE-cadherin is a substrate for tyrosine kinases in vivo and that its phosphorylation, together with that of associated Src, is increased by angiogenic stimulation. Physical association between Flk1, Src, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of VEGF-stimulated angiogenic processes.

Published
2005
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19. Protocadherin 12 (VE-cadherin 2) is expressed in endothelial, trophoblast, and mesangial cells

Author

Emmanuelle Tillet, Muriel Vernet, Hervé Pointu, Marie-Hélène Prandini, Stéphanie Bouillot, Philippe Huber, Christine Rampon, Ronald Frank, Laboratoire de développement et vieillissement de l'endothélium, Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Atelier de Transgenèse, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Chemical Biology, German Research Centre for Biotechnology, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Huber, Philippe

Subjects
Male, MESH: Trophoblasts, Cellular differentiation, MESH: Glycogen, MESH: Mice, Knockout, MESH: Cadherins, Mice, 0302 clinical medicine, MESH: Gene Expression Regulation, Developmental, MESH: Animals, MESH: Endothelial Cells, Mice, Knockout, 0303 health sciences, Cell adhesion molecule, Gene Expression Regulation, Developmental, Cell Differentiation, Cadherins, Glomerular Mesangium, Trophoblasts, medicine.anatomical_structure, MESH: Pluripotent Stem Cells, Female, Glycogen, Pluripotent Stem Cells, MESH: Cell Differentiation, Endothelium, MESH: Glomerular Mesangium, Protocadherin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, 03 medical and health sciences, medicine, Animals, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, Cadherin, MESH: Biological Markers, Trophoblast, Endothelial Cells, Cell Biology, Embryonic stem cell, Molecular biology, Protocadherins, MESH: Male, MESH: Cell Line, VE-cadherin, MESH: Female, 030217 neurology & neurosurgery, Biomarkers
Abstract

International audience; Protocadherin 12 protein (PCDH12, VE-cadherin 2) is a cell adhesion molecule that has been isolated from endothelial cells. Here, we have used Northern and Western blots, immunohistology, and flow cytometry to examine the distribution of PCDH12 in mouse tissues. It is an N-glycosylated protein of 150-kDa mass. In the endothelium, PCDH12 immunoreactivity was variable and dependent upon the vascular bed. In both the embryo and embryonic stem cell differentiation system, signals were localized in vasculogenic rather than angiogenic endothelium. In addition, the protein was strongly expressed in a subset of invasive cells of the placenta, which were identified as glycogen-rich trophoblasts. In adult mice, strong PCDH12 signals were observed in mesangial cells of kidney glomeruli whereas expression was not detected in other types of perivascular cells. As opposed to most protocadherins, PCDH12 is not expressed in early embryonic (day 12.5) and adult brains. As a first approach to obtain insight into PCDH12 function, we produced transgenic mice deficient in PCDH12, which were viable and fertile. They did not display any obvious histomorphological defects. We conclude that PCDH12 has a unique expression pattern and that its deficiency does not lead to conspicuous abnormalities. Moreover, PCDH12 is the first specific marker for both glycogen-rich trophoblasts and mesangial cells.

Published
2005
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20. The human VE-cadherin promoter is subjected to organ-specific regulation and is activated in tumour angiogenesis

Author

Marie-Hélène Prandini, Thomas Moll, Stéphanie Bouillot, Souhila Benkerri, Inge Dreher, Philippe Huber, Huber, Philippe, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Cardion

Subjects
Cancer Research, Angiogenesis, MESH: Base Sequence, medicine.disease_cause, MESH: Cadherins, Mice, 0302 clinical medicine, Neoplasms, MESH: Animals, MESH: Neoplasms, Promoter Regions, Genetic, MESH: Antigens, CD, MESH: Organ Specificity, 0303 health sciences, Neovascularization, Pathologic, Transfection, MESH: Gene Expression Regulation, Neoplastic, Cadherins, 3. Good health, Gene Expression Regulation, Neoplastic, Organ Specificity, 030220 oncology & carcinogenesis, Genetically modified mouse, MESH: Mice, Transgenic, Transgene, Molecular Sequence Data, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Article, 03 medical and health sciences, Antigens, CD, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Humans, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, Matrigel, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Cadherin, Molecular biology, VE-cadherin, Carcinogenesis, MESH: Neovascularization, Pathologic
Abstract

International audience; Vascular endothelial (VE)-cadherin is exclusively expressed at interendothelial junctions of normal and tumour vessels. In this report, we characterized the transcriptional activity of the human VE-cadherin promoter. Transient transfection assays revealed that sequences at positions --1135/-744 and -166/-5 base pairs are critical for promoter activity in endothelial cells. We show that specific sequences in the proximal region interact with Ets and Sp1 family members. Transgenic mice were created and the human VE-cadherin promoter was able to confer correct temporal and spatial expression on the LacZ gene in embryos. In adults, the transgene was specifically and strongly expressed in the lung, heart, ovary, spleen and kidney glomeruli, whereas expression was weak or absent in the vasculature of other organs, including the brain, thymus, liver and skeletal muscle. Neovessels in tumour grafts and Matrigel implants harboured strong stainings, indicating that promoter activity is enhanced in angiogenic situations. Furthermore, Matrigel and transfection assays showed that VE-cadherin promoter is subjected to bFGF induction. Transgene expression was also noticed in extravascular sites of the central nervous system, suggesting that silencer elements may be located elsewhere in the gene. These results are a first step towards addressing the organ- and tumour-specific regulation of the VE-cadherin gene.

Published
2005
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21. Specific AHNAK expression in brain endothelial cells with barrier properties

Author

Christian Delphin, Vincent Berezowski, Daniel Vittet, Benoit J. Gentil, Roméo Cecchelli, Chantal Rémy, Jacques Baudier, Olivier Feraud, Christelle Benaud, Baudier, Jacques, Mécanismes d'expression cellulaire des effecteurs humoraux, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Résonance magnétique nucléaire bioclinique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Laboratoire de développement et vieillissement de l'endothélium, and Association pour la Recherche contre le Cancer

Subjects
Male, MESH: Neoplasm Proteins, Physiology, Clinical Biochemistry, Cell Communication, MESH: Animals, Newborn, MESH: Tight Junctions, MESH: Blood-Brain Barrier, Mice, 0302 clinical medicine, Cytosol, MESH: Cytosol, Extracellular fluid, MESH: Up-Regulation, MESH: Animals, MESH: Endothelial Cells, 0303 health sciences, Tight junction, Brain Neoplasms, Brain, Cell Differentiation, Cell biology, Neoplasm Proteins, Up-Regulation, Protein Transport, MESH: Cattle, medicine.anatomical_structure, Blood-Brain Barrier, MESH: Brain Neoplasms, Choroid plexus, MESH: Neuroglia, MESH: Membrane Proteins, Neuroglia, MESH: Cell Differentiation, MESH: Protein Transport, Endothelium, MESH: Rats, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Phosphoproteins, Cell Line, Tight Junctions, MESH: Coculture Techniques, 03 medical and health sciences, MESH: Brain, MESH: Angiopoietin-1, MESH: Cell Communication, medicine, Low permeability, Angiopoietin-1, Animals, Rats, Wistar, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, Cell Membrane, Endothelial Cells, Membrane Proteins, Cell Biology, MESH: Rats, Wistar, Phosphoproteins, Coculture Techniques, MESH: Male, Rats, MESH: Cell Line, Animals, Newborn, Permeability (electromagnetism), MESH: Choroid Plexus, Immunology, Choroid Plexus, Zonula Occludens-1 Protein, Cattle, 030217 neurology & neurosurgery, Homeostasis, MESH: Cell Membrane
Abstract

The blood–brain barrier (BBB) is essential for maintaining brain homeostasis and low permeability. Because disruption of the BBB may contribute to many brain disorders, they are of considerable interests in the identification of the molecular mechanisms of BBB development and integrity. We here report that the giant protein AHNAK is expressed at the plasma membrane of endothelial cells (ECs) forming specific blood–tissue barriers, but is absent from the endothelium of capillaries characterized by extensive molecular exchanges between blood and extracellular fluid. In the brain, AHNAK is widely distributed in ECs with BBB properties, where it co-localizes with the tight junction protein ZO-1. AHNAK is absent from the permeable brain ECs of the choroid plexus and is down-regulated in permeable angiogenic ECs of brain tumors. In the choroid plexus, AHNAK accumulates at the tight junctions of the choroid epithelial cells that form the blood–cerebrospinal fluid (CSF) barrier. In EC cultures, the regulation of AHNAK expression and its localization corresponds to general criteria of a protein involved in barrier organization. AHNAK is up-regulated by angiopoietin-1 (Ang-1), a morphogenic factor that regulates brain EC permeability. In bovine cerebral ECs co-cultured with glial cells, AHNAK relocates from the cytosol to the plasma membrane when endothelial cells acquire BBB properties. Our results identify AHNAK as a protein marker of endothelial cells with barrier properties. © 2004 Wiley-Liss, Inc.

Published
2005
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22. Tracing the glycogen cells with protocadherin 12 during mouse placenta development.

Author

Bouillot S, Rampon C, Tillet E, and Huber P

Subjects
Animals, Biomarkers analysis, Cell Adhesion, Cell Lineage, Cell Movement, Decidua cytology, Decidua metabolism, Female, Mice, Mice, Inbred Strains, Protocadherins, Trophoblasts metabolism, Trophoblasts physiology, Cadherins analysis, Glycogen metabolism, Placentation, Pregnancy physiology, Trophoblasts chemistry
Abstract

Among the different trophoblast subtypes of the mouse placenta, the glycogen cells (GC) are one of the trophoblast subtypes that invade the decidua. We previously established that GC specifically expressed protocadherin 12 (PCDH12). In this paper, we investigated the origin of the PCDH12-positive cells and we characterized their fate in the maternal tissues. Our data indicate that they directly originate from the central part of the ectoplacental cone at embryonic day (E) 7.5. PCDH12-positive cells start to accumulate glycogen from E10.5 and the first migrating cells could be observed from this age. Unlike other placental and decidual cells, GC do not express P-cadherin, which may explain their migration properties in this organ. In the decidua, GC settle in the vicinity of the maternal vascular sinuses but do not incorporate in the endothelium. By the end of gestation (E17.5), most GC islets of the decidua enter into a lytic phase and form large lacunae. These lacunae, filled with glycogen, may provide a substantial source of energy at the end of gestation or during delivery. Our data suggest that spongiotrophoblasts and GC are two independent lineages and we bring insights into GC migration and fate.

Published
2006
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23. Brain death does not change epicardial action potentials and their response to ischemia-reperfusion in open-chest pigs.

Author

Christé G, Hadour G, Ovize M, and Ferrera R

Subjects
Animals, Arteries, Blood Pressure, Heart Rate, Heart Ventricles, Hemodynamics, Lactic Acid blood, Myocardial Reperfusion Injury blood, Norepinephrine blood, Reaction Time, Swine, Veins, Action Potentials, Brain Death blood, Brain Death physiopathology, Myocardial Reperfusion Injury physiopathology, Pericardium physiopathology
Abstract

Background: It is debated whether brain death (BD) causes transient functional ischemia. In this investigation we used monophasic action potential (AP) recording during BD as a sensitive means to assess: (i) whether ischemia was present; and (ii) the effect of BD on a subsequent ischemia-reperfusion challenge., Methods: In Period 1, BD was induced (BD group, 6 pigs) or not induced (sham maneuver, control [C] group, 6 pigs), and effects were followed for 3 hours. In Period 2, left anterior descending (LAD) coronary artery ligation ischemia was applied for 20 minutes to all hearts, followed by 60-minute reperfusion., Results: In Period 1, plasma norepinephrine was 3.1-, 6.3- and 5-fold greater in BD than in C at 1, 120 and 180 minutes, respectively, and systolic blood pressure was 26% greater at 1 minute and 35% at 120 minutes. The arteriovenous difference in lactate was similar or lower in BD than in C. In both groups, at all time-points, the action potential recording had a rectangular plateau shape and action potential duration (APD50) had a linear relationship to the cardiac inter-beat (RR) interval (R2 = 0.89 and 0.73, slope = 0.42 +/- 0.02 and 0.46 +/- 0.06 in BD and C, respectively). In Period 2, ischemia caused a similar (50%) APD shortening in BD and C. Restoration of the APD upon reperfusion was complete in both groups., Conclusions: Our findings suggest that BD does not cause direct cardiac ischemia and does not change the response of the heart to subsequent ischemia-reperfusion challenge.

Published
2006
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24. Platelet-activating factor increases VE-cadherin tyrosine phosphorylation in mouse endothelial cells and its association with the PtdIns3'-kinase.

Author

Hudry-Clergeon H, Stengel D, Ninio E, and Vilgrain I

Subjects
Adherens Junctions drug effects, Adherens Junctions ultrastructure, Animals, Antigens, CD, Benzoquinones, Cadherins chemistry, Cell Line, Embryo, Mammalian, Endothelial Cells chemistry, Endothelial Cells ultrastructure, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Fluorescent Antibody Technique, Heart, Immunosorbent Techniques, Intracellular Signaling Peptides and Proteins pharmacology, Lactams, Macrocyclic, Mice, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Phosphorylation, Platelet Membrane Glycoproteins analysis, Platelet Membrane Glycoproteins genetics, Platelet Membrane Glycoproteins physiology, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Quinones pharmacology, RNA, Messenger analysis, Receptors, G-Protein-Coupled analysis, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled physiology, Reverse Transcriptase Polymerase Chain Reaction, Rifabutin analogs & derivatives, Tyrphostins pharmacology, Cadherins metabolism, Endothelial Cells metabolism, Phosphatidylinositol 3-Kinases metabolism, Platelet Activating Factor pharmacology, Tyrosine metabolism
Abstract

Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in endothelial permeability. This study was designed to characterize PAF receptor (PAF-R) expression and its specific contribution to the modifications of adherens junctions in mouse endothelial cells. We demonstrated that PAF-R was expressed in mouse endothelial cells and was functionally active in stimulating p42/p44 MAPK and phosphatidylinositol 3-kinase (PtdIns3'-kinase)/Akt activities. Treatment of cells with PAF induced a rapid time- and dose-dependent (10(-7) to 10(-10) M) increase in tyrosine phosphorylation of a subset of proteins ranging from 90 to 220 kDa, including the VE-cadherin, the latter effect being prevented by the tyrosine kinase inhibitors herbimycin A and bis-tyrphostin. We demonstrated that PAF promoted formation of multimeric aggregates of VE-cadherin with PtdIns3'-kinase, which was also inhibited by herbimycin and bis-tyrphostin. Finally, we show by immunostaining of endothelial cells VE-cadherin that PAF dissociated adherens junctions. The present data provide the first evidence that treatment of endothelial cells with PAF promoted activation of tyrosine kinases and the VE-cadherin tyrosine phosphorylation and PtdIns3'-kinase association, which ultimately lead to the dissociation of adherens junctions. Physical association between PtdIns3'-kinase, serving as a docking protein, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of PAF-induced cellular activation.

Published
2005
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25. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues.

Author

Lambeng N, Wallez Y, Rampon C, Cand F, Christé G, Gulino-Debrac D, Vilgrain I, and Huber P

Subjects
Animals, Cell Extracts chemistry, Cell Line, Endothelial Cells chemistry, Endothelial Cells metabolism, Endothelium, Vascular cytology, Female, Gonadotropins, Equine pharmacology, Humans, Mice, Mice, Inbred C57BL, Ovary drug effects, Ovary metabolism, Phosphorylation drug effects, Proteins chemistry, Proteins metabolism, Proto-Oncogene Proteins pp60(c-src) antagonists & inhibitors, Proto-Oncogene Proteins pp60(c-src) metabolism, Umbilical Veins cytology, Uterus drug effects, Uterus metabolism, Vanadates administration & dosage, Vanadates pharmacology, Vascular Endothelial Growth Factor Receptor-2 metabolism, Cadherins chemistry, Cadherins metabolism, Endothelium, Vascular chemistry, Endothelium, Vascular metabolism, Neovascularization, Physiologic physiology, Phosphotyrosine metabolism
Abstract

Vascular endothelial-cadherin (VE-cadherin) plays a key role in angiogenesis and in vascular permeability. The regulation of its biological activity may be a central mechanism in normal or pathological angiogenesis. VE-cadherin has been shown to be phosphorylated on tyrosine in vitro under various conditions, including stimulation by VEGF. In the present study, we addressed the question of the existence of a tyrosine phosphorylated form of VE-cadherin in vivo, in correlation with the quiescent versus angiogenic state of adult tissues. Phosphorylated VE-cadherin was detected in mouse lung, uterus, and ovary but not in other tissues unless mice were injected with peroxovanadate to block protein phosphatases. Remarkably, VE-cadherin tyrosine phosphorylation was dramatically increased in uterus and ovary, and not in other organs, during PMSG/hCG-induced angiogenesis. In parallel, we observed an increased association of VE-cadherin with Flk1 (VEGF receptor 2) during hormonal angiogenesis. Additionally, Src kinase was constitutively associated with VE-cadherin in both quiescent and angiogenic tissues and increased phosphorylation of VE-cadherin-associated Src was detected in uterus and ovary after hormonal treatment. Src-VE-cadherin association was detected in cultured endothelial cells, independent of VE-cadherin phosphorylation state and Src activation level. In this model, Src inhibition impaired VEGF-induced VE-cadherin phosphorylation, indicating that VE-cadherin phosphorylation was dependent on Src activation. We conclude that VE-cadherin is a substrate for tyrosine kinases in vivo and that its phosphorylation, together with that of associated Src, is increased by angiogenic stimulation. Physical association between Flk1, Src, and VE-cadherin may thus provide an efficient mechanism for amplification and perpetuation of VEGF-stimulated angiogenic processes.

Published
2005
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26. Expressional regulation of the angiopoietin-1 and -2 and the endothelial-specific receptor tyrosine kinase Tie2 in adrenal atrophy: a study of adrenocorticotropin-induced repair.

Author

Féraud O, Mallet C, and Vilgrain I

Subjects
Adrenal Cortex, Adrenal Glands drug effects, Adrenocorticotropic Hormone pharmacology, Angiopoietin-1, Angiopoietin-2, Animals, Atrophy, Dexamethasone pharmacology, Female, Glucocorticoids pharmacology, Mice, Pituitary-Adrenal System physiology, Receptor, TIE-2, Adrenal Glands metabolism, Adrenal Glands pathology, Angiogenesis Inducing Agents metabolism, Membrane Glycoproteins metabolism, Receptor Protein-Tyrosine Kinases metabolism
Abstract

Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization, and to function in concert with vascular endothelial growth factor. Adrenal gland has an intense capillary network that regulation remains to be documented. Recently, we demonstrated that vascular endothelial growth factor, and its receptors are expressed in mouse adrenal in vivo, but no detailed study on Ang expression in the adrenal has been reported. The present study shows the expression of Tie2 receptors, Ang-1, and its endogenous antagonist, Ang-2 in mouse adrenal in vivo. Immunohistochemistry disclosed that Tie2 colocalized with platelet-endothelial-cell-adhesion-molecule in endothelial cells from normal mouse adrenal. Daily administration of dexamethasone (DEX) (0.5 mg/100 g body weight.d) for 6 d in mice, decreased steroidogenic function of adrenal as shown by inhibition of the 36-kDa ACTH receptor protein expression, and decreased plasma corticosterone level [control from 465 +/- 35 ng/ml to 114 +/- 18 ng/ml in DEX group (P < 0.001)]. Using semiquantitative RT-PCR, we demonstrate that DEX treatment down regulates Ang-1 mRNA levels by 3- to 4-fold. No significant changes in Ang-2 were detected between control and DEX groups, resulting in an altered Ang-2 to Ang-1 relative ratio. The Tie2 receptor was also found to be down-regulated in DEX group at both mRNA and protein level. ACTH was found to play a causal role in DEX-induced decrease in Ang-1/Tie2 system, because 7 d treatment with long acting 1-39 ACTH (30 IU/kg x d) increased Ang-1, Tie2 expression, and plasma corticosterone back to control levels. These results reinforce the role of ACTH in the regulation of angiogenic factors in adrenal gland and suggest that the Ang/Tie2 system might represent a key player for stabilization of adrenal endothelium.

Published
2003
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27. The age-dependent vasodilatation and endothelial calcium influx induced by elastin peptides are modulated by extracellular glucose level.

Author

Faury G, Robert L, and Verdetti J

Subjects
Animals, Aorta, Thoracic metabolism, Elastin pharmacology, Female, Humans, In Vitro Techniques, Myography, Patch-Clamp Techniques, Rats, Rats, Wistar, Umbilical Veins metabolism, Vasodilation drug effects, Aging metabolism, Calcium metabolism, Elastin physiology, Endothelium, Vascular metabolism, Glucose metabolism, Vasodilation physiology
Abstract

Elastin peptides have been shown to produce many biological effects on various cell types, including an endothelium- and NO-dependent vasodilatation mediated by extracellular calcium influx and intracellular calcium elevation. Under normal concentration of extracellular glucose, the vasodilatory effect is observed in adult rats and is lost with age. Here, we have studied the consequences of extracellular glucose level changes on these effects triggered by elastin peptides (10(-4)-10(-3) mg ml(-1)), on 6- and 30-month-old rats, using the tension myography and the patch-clamp techniques. Our results show that low (0 mM) or high (33 mM) extracellular glucose concentrations abolish the extracellular calcium influx induced, under normal glucose level (11 mM), by the elastin peptides in cultured human endothelial cells. Also, low or high glucose abolish the vasodilatory action of elastin peptides observed on aorta rings from adult rats under normal glucose concentration. On the contrary, a dilation of aged rat aorta is observed in the presence of elastin peptides and high glucose, whereas such dilation is not observed when the elastin peptides are added in the presence of normal glucose concentration. In aging, a restoration by high glucose of the NO-dependent vasodilatation induced by elastin peptides could enhance the production of damaging peroxynitrite, potentially altering the structure and function of the blood vessels. These results could be of importance in the evaluation and treatment of aged patients with pathophysiological dysregulations of the circulating glucose level, such as in diabetes, age-related glucose intolerance, or low glucose levels caused by inappropriate glucose control treatments.

Published
2003
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