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1. Long non-coding RNA Neat1 and paraspeckle components are translational regulators in hypoxia

Author

Anne-Claire Godet, Emilie Roussel, Florian David, Fransky Hantelys, Florent Morfoisse, Joffrey Alves, Françoise Pujol, Isabelle Ader, Edouard Bertrand, Odile Burlet-Schiltz, Carine Froment, Anthony K Henras, Patrice Vitali, Eric Lacazette, Florence Tatin, Barbara Garmy-Susini, and Anne-Catherine Prats

Subjects
translational control, lncRNA, Neat1, cardiomyocyte, angiogenic growth factor, hypoxia, Medicine, Science, Biology (General), QH301-705.5
Abstract

Internal ribosome entry sites (IRESs) drive translation initiation during stress. In response to hypoxia, (lymph)angiogenic factors responsible for tissue revascularization in ischemic diseases are induced by the IRES-dependent mechanism. Here, we searched for IRES trans-acting factors (ITAFs) active in early hypoxia in mouse cardiomyocytes. Using knock-down and proteomics approaches, we show a link between a stressed-induced nuclear body, the paraspeckle, and IRES-dependent translation. Furthermore, smiFISH experiments demonstrate the recruitment of IRES-containing mRNA into paraspeckle during hypoxia. Our data reveal that the long non-coding RNA Neat1, an essential paraspeckle component, is a key translational regulator, active on IRESs of (lymph)angiogenic and cardioprotective factor mRNAs. In addition, paraspeckle proteins p54nrb and PSPC1 as well as nucleolin and RPS2, two p54nrb-interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as a platform to recruit IRES-containing mRNAs and possibly host IRESome assembly. Polysome PCR array shows that Neat1 isoforms regulate IRES-dependent translation and, more widely, translation of mRNAs involved in stress response.

Published
2022
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2. Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation in early hypoxia

Author

Fransky Hantelys, Anne-Claire Godet, Florian David, Florence Tatin, Edith Renaud-Gabardos, Françoise Pujol, Leila H Diallo, Isabelle Ader, Laetitia Ligat, Anthony K Henras, Yasufumi Sato, Angelo Parini, Eric Lacazette, Barbara Garmy-Susini, and Anne-Catherine Prats

Subjects
translational control, hypoxia, angiogenesis, cardiomyocyte, IRES, vasohibin, Medicine, Science, Biology (General), QH301-705.5
Abstract

Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart.

Published
2019
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3. Paclitaxel induces lymphatic endothelial cells autophagy to promote metastasis

Author

Anne-Catherine Prats, Barbara Garmy-Susini, Melinda Alves, Laurent O. Martinez, Charlotte Vaysse, Souad Najib, Anne Gomez-Brouchet, Julie Guillermet-Guibert, Eric Lacazette, Nicole Therville, Charlotte Chollet, Florence Tatin, Camille Franchet, Audrey Zamora, Tiffany Fougeray, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Garmy-Susini, Barbara, ProdInra, Migration, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, medicine.medical_treatment, Metastasis, chemistry.chemical_compound, Breast cancer, 0302 clinical medicine, Cell Movement, Cancer, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, lcsh:Cytology, Chloroquine, 3. Good health, Endothelial stem cell, Lymphatic Endothelium, Lymphatic system, medicine.anatomical_structure, Paclitaxel, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Female, Lymph, Sentinel Lymph Node, Endothelium, Cell Survival, government.form_of_government, Immunology, Médecine humaine et pathologie, Breast Neoplasms, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Line, Tumor, Autophagy, Cell Adhesion, medicine, Humans, lcsh:QH573-671, Cell Proliferation, 030304 developmental biology, Chemotherapy, business.industry, Endothelial Cells, Cell Biology, medicine.disease, chemistry, Drug Resistance, Neoplasm, government, Cancer research, Human health and pathology, Lysosomes, business, Proto-Oncogene Proteins c-akt, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Cytotoxic therapy for breast cancer inhibits the growth of primary tumors, but promotes metastasis to the sentinel lymph nodes through the lymphatic system. However, the effect of first-line chemotherapy on the lymphatic endothelium has been poorly investigated. In this study, we determined that paclitaxel, the anti-cancer drug approved for the treatment of metastatic or locally advanced breast cancer, induces lymphatic endothelial cell (LEC) autophagy to increase metastases. While paclitaxel treatment was largely efficacious in inhibiting LEC adhesion, it had no effect on cell survival. Paclitaxel inhibited LEC migration and branch point formation by inducing an autophagy mechanism independent of Akt phosphorylation. In vivo, paclitaxel mediated a higher permeability of lymphatic endothelium to tumor cells and this effect was reversed by chloroquine, an autophagy-lysosome inhibitor. Despite a strong effect on reducing tumor size, paclitaxel significantly increased metastasis to the sentinel lymph nodes. This effect was restricted to a lymphatic dissemination, as chemotherapy did not affect the blood endothelium. Taken together, our findings suggest that the lymphatic system resists to chemotherapy through an autophagy mechanism to promote malignant progression and metastatic lesions. This study paves the way for new combinative therapies aimed at reducing the number of metastases.

Published
2019
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4. Circular RNA, the Key for Translation

Author

Eric Lacazette, Anne-Catherine Prats, Leila Diallo, Florence Tatin, Barbara Garmy-Susini, Emilie Roussel, and Florian David

Subjects
0301 basic medicine, m6A, translation, Review, 010501 environmental sciences, 01 natural sciences, Ribosome, lcsh:Chemistry, chemistry.chemical_compound, 0302 clinical medicine, IRES, anatomy_morphology, circRNA, lcsh:QH301-705.5, Spectroscopy, Chemistry, EIF4G, Translation (biology), General Medicine, Computer Science Applications, Cell biology, ribosome, 030220 oncology & carcinogenesis, MIRES, 3′UTR, Internal Ribosome Entry Sites, Poly(A)-Binding Proteins, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Eukaryotic translation, Circular RNA, Polysome, Initiation factor, Humans, RNA, Messenger, Physical and Theoretical Chemistry, Molecular Biology, 0105 earth and related environmental sciences, RNA circularization, Organic Chemistry, other, RNA, Circular, Internal ribosome entry site, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Protein Biosynthesis, Eukaryotic Initiation Factor-4G, Ribosomes
Abstract

It was thought until the 1990s that the eukaryotic translation machinery was unable to translate a circular RNA. However internal ribosome entry sites (IRESs) and m6A-induced ribosome engagement sites (MIRESs) were discovered, promoting 5’end-independent translation initiation. Today a new family of so-called “non-coding” circular RNAs (circRNAs) has emerged, revealing the pivotal role of 5’end-independent translation. CircRNAs have a strong impact on translational control via their sponge function, and form a new mRNA family as they are translated into proteins with pathophysiological roles. While there is no more doubt about translation of covalently closed circRNA, the linearity of canonical mRNA is only theoretical: it has been shown for more than thirty years that polysomes exhibit a circular form and mRNA functional circularization has been demonstrated in the 1990s by the interaction of initiation factor eIF4G with poly(A) binding protein. More recently, additional mechanisms of 3’-5’ interaction have been reported, including m6A modification. Functional circularization enhances translation via ribosome recycling and acceleration of the translation initiation rate. This update of covalently and non-covalently circular mRNA translation landscape shows that RNA circular shape might be the rule for translation with an important impact on disease development and biotechnological applications.

Published
2020
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5. Lymphatic Vasculature Requires Estrogen Receptor- Signaling to Protect From Lymphedema

Author

Anne-Catherine Prats, Françoise Lenfant, Frédéric Boudou, Raphaël Métivier, Charlotte Vaysse, Anne-Claire Godet, David Dubuc, Katia Grenier, Julie Guillermet-Guibert, Françoise Pujol, Florent Morfoisse, Eric Lacazette, Julie Malloizel-Delaunay, Nicole Therville, Benoit Chaput, Fabienne De Toni, Barbara Garmy-Susini, Florence Tatin, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Toulouse 1 Capitole (UT1), Équipe Micro et nanosystèmes HyperFréquences Fluidiques (LAAS-MH2F), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Ligue Regionale Contre le Cancer [RPT15002BBA], foundation ARC pour la Recherche sur le Cancer [RAC15003BBA], IDEX Paul Sabatier Federal University [RGE14001BBA], Toulouse Cancer Sante Fondation, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1)

Subjects
0301 basic medicine, medicine.medical_specialty, mice, medicine.drug_class, Secondary lymphedema, government.form_of_government, Estrogen receptor, lymphatic vessels, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Receptor, [SDV.GEN]Life Sciences [q-bio]/Genetics, Chemistry, lymphedema, endothelial cells, 3. Good health, Vascular endothelial growth factor, animals, Lymphatic Endothelium, 030104 developmental biology, Endocrinology, Lymphatic system, Estrogen, 030220 oncology & carcinogenesis, government, medicine.symptom, Cardiology and Cardiovascular Medicine, Tamoxifen, medicine.drug
Abstract

Objective— Estrogens exert beneficial effect on the blood vascular system. However, their role on the lymphatic system has been poorly investigated. We studied the protective effect of the 17β estradiol—the most potent endogenous estrogen—in lymphedema—a lymphatic dysfunction, which results in a massive fluid and fat accumulation in the limb. Approach and Results— Screening of DNA motifs able to mobilize ERs (estrogen receptors) and quantitative real-time polymerase chain reaction analysis revealed that estradiol promotes transcriptional activation of lymphangiogenesis-related gene expression including VEGF (vascular endothelial growth factor)-D, VEGFR (VEGF receptor)-3, lyve-1, and HASs (hyaluronan synthases). Using an original model of secondary lymphedema, we observed a protective effect of estradiol on lymphedema by reducing dermal backflow—a representative feature of the pathology. Blocking ERα by tamoxifen—the selective estrogen modulator—led to a remodeling of the lymphatic network associated with a strong lymphatic leakage. Moreover, the protection of lymphedema by estradiol treatment was abrogated by the endothelial deletion of the receptor ERα in Tie2-Cre; ERα lox/lox mice, which exhibit dilated lymphatic vessels. This remodeling correlated with a decrease in lymphangiogenic gene expression. In vitro, blocking ERα by tamoxifen in lymphatic endothelial cells decreased cell–cell junctions, inhibited migration and sprouting, and resulted in an inhibition of Erk but not of Akt phosphorylation. Conclusions— Estradiol protection from developing lymphedema is mediated by an activation of its receptor ERα and is antagonized by tamoxifen. These findings reveal a new facet of the estrogen influence in the management of the lymphatic system and provide more evidence that secondary lymphedema is worsened by hormone therapy.

Published
2018
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6. Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart

Author

Philippe Valet, Benoit Lebas, Bernard Masri, Pierre Sicard, Barbara Garmy-Susini, Jerome Roncalli, Fransky Hantelys, Françoise Pujol, Oksana Kunduzova, Anne-Catherine Prats, Xavier Chaufour, Edith Renaud-Gabardos, Angelo Parini, Florence Tatin, Denis Calise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse, ANEXPLO / CREFRE, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-SANOFI Recherche-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aventis, Laboratoire de Physiopathologie et de Pharmacologie Cardiovasculaire Expérimentale (LPPCE), Université de Bourgogne (UB), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Analytic and Computational Research, Inc. - Earth Sciences (ACRI-ST), Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Masri, Bernard

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Angiogenesis, FGF2, Genetic enhancement, [SDV]Life Sciences [q-bio], Myocardial Ischemia, Gene Expression, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Bioinformatics, MESH: Gene Order, Mice, angiogenesis, Transduction, Genetic, IRES, MESH: Genetic Vectors, Gene Order, Drug Discovery, Gene Regulatory Networks, MESH: Animals, MESH: Endothelial Cells, Myocardial infarction, gene transfer, ComputingMilieux_MISCELLANEOUS, MESH: Gene Regulatory Networks, MESH: Lentivirus, Cardioprotection, Neovascularization, Pathologic, Gene Transfer Techniques, MESH: Transduction, Genetic, 3. Good health, Apelin, [SDV] Life Sciences [q-bio], apelin, MESH: Fibrosis, cardiovascular system, Molecular Medicine, MESH: Myocardial Ischemia, Original Article, Fibroblast Growth Factor 2, Cardiac function curve, MESH: Gene Expression, Genetic Vectors, lentivector, Cardiomegaly, Context (language use), MESH: Gene Transfer Techniques, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Sarcoplasmic Reticulum Calcium-Transporting ATPases, 03 medical and health sciences, MESH: Sarcoplasmic Reticulum Calcium-Transporting ATPases, combined therapy, Genetics, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, MESH: Mice, Pharmacology, MESH: Genetic Therapy, MESH: Fibroblast Growth Factor 2, MESH: Transcriptome, Lentivirus, fibrosis, Endothelial Cells, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Genetic Therapy, medicine.disease, ischemic heart disease, Disease Models, Animal, SERCA2, 030104 developmental biology, MESH: Apelin, Heart failure, Immunology, MESH: Cardiomegaly, MESH: Disease Models, Animal, Transcriptome, MESH: Neovascularization, Pathologic
Abstract

International audience; Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large-scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation.

Published
2018
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7. Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

Author

Eric Lacazette, Barbara Garmy-Susini, Angelo Parini, Edith Renaud-Gabardos, Laetitia Ligat, Anne Catherine Prats, Florian David, Leila Diallo, Fransky Hantelys, Isabelle Ader, Florence Tatin, Françoise Pujol, Anthony K. Henras, Anne Claire Godet, and Yasufumi Sato

Subjects
Transcriptome, Messenger RNA, Internal ribosome entry site, Angiogenesis, Gene expression, fungi, medicine, Trans-acting, Hypoxia (medical), medicine.symptom, Biology, FGF1, Cell biology
Abstract

Hypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.

Published
2018
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8. Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction

Author

Anne-Catherine Prats, Barbara Garmy-Susini, Anne-Claire Godet, Florence Tatin, Fransky Hantelys, Philippe Valet, Françoise Pujol, Bernard Masri, Florent Morfoisse, Edith Renaud-Gabardos, Fanny Viars, Denis Calise, Atherosclerose : Determinisme Cellulaire et Moleculaire, Consequences Fonctionnelles, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hormones, facteurs de croissance et physiopathologie vasculaire, IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Centre for Oncology and Molecular Medicine, University of Dundee-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT)

Subjects
0301 basic medicine, medicine.medical_specialty, Angiogenesis, government.form_of_government, [SDV]Life Sciences [q-bio], Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Lymphatic vessel, Tissue homeostasis, ComputingMilieux_MISCELLANEOUS, business.industry, General Medicine, 3. Good health, Apelin, Lymphangiogenesis, Lymphatic Endothelium, 030104 developmental biology, Lymphatic system, medicine.anatomical_structure, government, Cancer research, Cardiology, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Lymphatic endothelium serves as a barrier to control fluid balance and immune cell trafficking to maintain tissue homeostasis. Long-term alteration of lymphatic vasculature promotes edema and fibrosis, which is an aggravating factor in the onset of cardiovascular diseases such as myocardial infarction. Apelin is a bioactive peptide that plays a central role in angiogenesis and cardiac contractility. Despite an established role of apelin in lymphangiogenesis, little is known about its function in the cardiac lymphatic endothelium. Here, we show that apelin and its receptor APJ were exclusively expressed on newly formed lymphatic vasculature in a pathological model of myocardial infarction. Using an apelin-knockout mouse model, we identified morphological and functional defects in lymphatic vasculature associated with a proinflammatory status. Surprisingly, apelin deficiency increased the expression of lymphangiogenic growth factors VEGF-C and VEGF-D and exacerbated lymphangiogenesis after myocardial infarction. Conversely, the overexpression of apelin in ischemic heart was sufficient to restore a functional lymphatic vasculature and to reduce matrix remodeling and inflammation. In vitro, the expression of apelin prevented the alteration of cellular junctions in lymphatic endothelial cells induced by hypoxia. In addition, we demonstrated that apelin controls the secretion of the lipid mediator sphingosine-1-phosphate in lymphatic endothelial cells by regulating the level of expression of sphingosine kinase 2 and the transporter SPNS2. Taken together, our results show that apelin plays a key role in lymphatic vessel maturation and stability in pathological settings. Thus, apelin may represent a novel candidate to prevent pathological lymphatic remodeling in diseases.

Published
2017
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9. Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells

Author

Elisabeth Génot, Ellen Van Obberghen-Schilling, Christine Varon, IJsbrand M. Kramer, Samantha Fernandez-Sauze, Edith Reuzeau, Violaine Moreau, Florence Tatin, Atherosclerose : Determinisme Cellulaire et Moleculaire, Consequences Fonctionnelles, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), European Institute of Chemistry and Biology, Université Sciences et Technologies - Bordeaux 1, Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, RHOA, Podosome, MESH: Matrix Metalloproteinases, Smad Proteins, CDC42, SMAD, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Phosphatidylinositol 3-Kinases, Transforming Growth Factor beta, MESH: Animals, MESH: Endothelial Cells, cdc42 GTP-Binding Protein, Cytoskeleton, Aorta, 0303 health sciences, biology, 030302 biochemistry & molecular biology, MESH: Aorta, Articles, Cell biology, Endothelial stem cell, MESH: Cattle, src-Family Kinases, Matrix Metalloproteinase 9, Cdc42 GTP-Binding Protein, MESH: Protein Biosynthesis, Signal Transduction, MESH: rhoA GTP-Binding Protein, Matrix Metalloproteinases, Membrane-Associated, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, MESH: Cytoskeleton, Animals, Humans, MESH: Matrix Metalloproteinases, Membrane-Associated, Molecular Biology, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: cdc42 GTP-Binding Protein, MESH: Humans, Endothelial Cells, MESH: Smad Proteins, MESH: Matrix Metalloproteinase 9, Cell Biology, Transforming growth factor beta, MESH: 1-Phosphatidylinositol 3-Kinase, Matrix Metalloproteinases, MESH: src-Family Kinases, Protein Biosynthesis, biology.protein, Cattle, rhoA GTP-Binding Protein
Abstract

International audience; Cytoskeletal rearrangements are central to endothelial cell physiology and are controlled by soluble factors, matrix proteins, cell-cell interactions, and mechanical forces. We previously reported that aortic endothelial cells can rearrange their cytoskeletons into complex actin-based structures called podosomes when a constitutively active mutant of Cdc42 is expressed. We now report that transforming growth factor beta (TGF-beta) promotes podosome formation in primary aortic endothelial cells. TGF-beta-induced podosomes assembled together into large ring- or crescent-shaped structures. Their formation was dependent on protein synthesis and required functional Src, phosphatidylinositide 3-kinase, Cdc42, RhoA, and Smad signaling. MT1-MMP and metalloprotease 9 (MMP9), both upregulated by TGF-beta, were detected at sites of podosome formation, and MT1-MMP was found to be involved in the local degradation of extracellular matrix proteins beneath the podosomes and required for the invasion of collagen gels by endothelial cells. We propose that TGF-beta plays an important role in endothelial cell physiology by inducing the formation of podosomal structures endowed with metalloprotease activity that may contribute to arterial remodeling.

Published
2006
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10. Sodium fluoride induces podosome formation in endothelial cells.

Author

Florence Tatin and Florence Grise

Subjects
*ENDOTHELIUM, *SODIUM fluoride, *CYTOSKELETON, *INTEGRINS, *EXTRACELLULAR matrix proteins, *ORGANELLES
Abstract

Background information. Fluoride is a well-known G-protein activator. Exposure of cultured cells to its derivatives results in actin cytoskeleton remodelling. Podosomes are actin-based structures endowed with adhesion and matrix-degradation functions. This study investigates actin cytoskeleton reorganization induced by fluoride in endothelial cells. Results. Treatment of cultured endothelial cells with sodium fluoride (NaF) results in a rapid and potent stimulation of podosome formation. Furthermore, we show that Cdc42 (cell-division cycle 42), Rac1 and RhoA activities are stimulated in NaF-treated cells. However, podosome assembly is dependent on Cdc42 and Rac1, but not RhoA. Although the sole activation of Cdc42 is sufficient to induce individual podosomes, a balance between RhoGTPase activities regulates podosome formation in response to NaF, which in this case are often found in groups or rosettes. As in other models, podosome formation in endothelial cells exposed to NaF also involves Src. Finally, we demonstrate that NaF-induced podosomes are fully competent for matrix protein degradation. Conclusions. Taken together, our findings establish NaF as a novel inducer of podosomes in endothelial cells in vitro. [ABSTRACT FROM AUTHOR]

Published
2010
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11. The Impact of Estrogen Receptor in Arterial and Lymphatic Vascular Diseases

Author

Coralie Fontaine, Florent Morfoisse, Florence Tatin, Audrey Zamora, Rana Zahreddine, Daniel Henrion, Jean-François Arnal, Françoise Lenfant, and Barbara Garmy-Susini

Subjects
Estrogen Receptor alpha, Estrogens, Review, Arteries, arterial, endothelial cells, lcsh:Chemistry, lymphatic, Sex Factors, lcsh:Biology (General), lcsh:QD1-999, Receptors, Estrogen, Animals, Humans, Disease Susceptibility, Endothelium, Vascular Diseases, lcsh:QH301-705.5, hormones, hormone substitutes, and hormone antagonists, Biomarkers, ERα, Lymphatic Vessels
Abstract

The lower incidence of cardiovascular diseases in pre-menopausal women compared to men is well-known documented. This protection has been largely attributed to the protective effect of estrogens, which exert many beneficial effects against arterial diseases, including vasodilatation, acceleration of healing in response to arterial injury, arterial collateral growth and atheroprotection. More recently, with the visualization of the lymphatic vessels, the impact of estrogens on lymphedema and lymphatic diseases started to be elucidated. These estrogenic effects are mediated not only by the classic nuclear/genomic actions via the specific estrogen receptor (ER) α and β, but also by rapid extra-nuclear membrane-initiated steroid signaling (MISS). The ERs are expressed by endothelial, lymphatic and smooth muscle cells in the different vessels. In this review, we will summarize the complex vascular effects of estrogens and selective estrogen receptor modulators (SERMs) that have been described using different transgenic mouse models with selective loss of ERα function and numerous animal models of vascular and lymphatic diseases.

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