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

Author

Athanasia Liabotis, Corinne Ardidie-Robouant, Philippe Mailly, Samaher Besbes, Charly Gutierrez, Yoann Atlas, Laurent Muller, Stéphane Germain, and Catherine Monnot

Subjects
angiopoietin-like 4, vascular endothelial growth factor, angiogenesis, adherens junction, in vitro 3D model, vascularization, Biology (General), QH301-705.5
Abstract

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

Published
2022
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2. Scavenger Receptor Cysteine-Rich domains of Lysyl Oxidase-Like2 regulate endothelial ECM and angiogenesis through non-catalytic scaffolding mechanisms

Author

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

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

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

Published
2023
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3. Papillary and Reticular Fibroblasts Generate Distinct Microenvironments that Differentially Impact Angiogenesis

Author

Sandrine Hughes, Philippe Mailly, Closs B, Corinne Ardidie-Robouant, Benjamin Gillet, A. Mauroux, Joncour P, Sylvie Bordes, Liabotis A, Stéphane Germain, Catherine Monnot, L. Marchand, Laurent Muller, Florence Ruggiero, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), R&D Department, SILAB, and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
0303 health sciences, education.field_of_study, Chemistry, Angiogenesis, [SDV]Life Sciences [q-bio], Population, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Dermis, 030220 oncology & carcinogenesis, Reticular connective tissue, Gene expression, medicine, Fibroblast, education, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Reticular Dermis, 030304 developmental biology
Abstract

Papillary and reticular dermis show distinct extracellular matrix (ECM) and vascularization, and fibroblasts isolated from these compartments have different gene expression patterns and behaviour in vitro. However, due to lack of relevant models, the contribution of skin fibroblast sub-populations to vascularization remains unknown. We thus cultured human papillary and reticular fibroblasts as cell sheets. Differential transcriptomic analysis was performed by RNA sequencing to characterize their microenvironment. Bioinformatic analysis revealed that each fibroblast population expressed specific angiogenesis and matrisome gene expression signatures resulting in specific ECM that differed both in composition and structure. The impact of secreted and ECM-bound factors was then assessed using 3D angiogenesis assays. When co-cultivated with endothelial cells, the papillary and reticular microenvironments induced the formation of distinct capillary networks mimicking the characteristics of vasculature of native dermis subcompartments (vessel diameter and density, number of branch points). Whereas conditioned media of papillary fibroblasts displayed intrinsic high angiogenic potential, reticular ones only contributed to capillary formation induced by exogenous VEGF. These results show that skin fibroblast populations regulate angiogenesis via both secreted and ECM-bound factors. Our work emphasizes the importance of papillary and reticular fibroblasts, not only for modelling dermis microenvironment but also for its vascularization.

Published
2022

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

Author

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

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

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

Published
2021
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6. VEGF-A plasma levels are associated with microvascular obstruction in patients with ST-segment elevation myocardial infarction

Author

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

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

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

Published
2019
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7. Interaction of the coiled‐coil domain with glycosaminoglycans protects angiopoietin‐like 4 from proteolysis and regulates its antiangiogenic activity

Author

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

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

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

Published
2008
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8. The interaction of heparan sulfate proteoglycans with endothelial transglutaminase-2 limits VEGF165-induced angiogenesis

Author

Laurent Muller, Hugues Lortat-Jacob, Corinne Ardidie-Robouant, Nathan Beckouche, Stéphane Germain, Sarah Berndt, Catherine Monnot, Julie Hardouin, Virginie Lelarge, Gerry Melino, Marine Bignon, A. Barret, Cathy Pichol-Thievend, Thomas Mathivet, Marion Garand, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Leicester, Institut de biologie structurale (IBS - UMR 5075 ), 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)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Vascular Endothelial Growth Factor A, Angiogenesis, Transglutaminase-2, VEGF165, Neovascularization, Physiologic, Heparan sulfate, Mice, Transgenic, Biology, Fibroblast growth factor, Biochemistry, Retina, Extracellular matrix, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cell Movement, GTP-Binding Proteins, Human Umbilical Vein Endothelial Cells, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein Glutamine gamma Glutamyltransferase 2, Therapeutic angiogenesis, Gene Silencing, Settore BIO/10, Phosphorylation, Molecular Biology, Cells, Cultured, 030304 developmental biology, Sprouting angiogenesis, 0303 health sciences, Matrigel, Transglutaminases, Retinal Vessels, Cell Biology, Surface Plasmon Resonance, Molecular biology, Vascular endothelial growth factor, carbohydrates (lipids), Mice, Inbred C57BL, chemistry, 030220 oncology & carcinogenesis, Proteoglycans, Endothelium, Vascular, Heparan Sulfate Proteoglycans, Signal Transduction
Abstract

International audience; Sprouting angiogenesis is stimulated by vascular endothelial growth factor (VEGF165) that is localized in the extracellular matrix (ECM) and binds to heparan sulfate (HS)-bearing proteins known as heparan sulfate proteoglycans (HSPGs). VEGF165 presentation by HSPGs enhances VEGF receptor-2 (VEGFR2) signaling. We investigated the effect of TG2, which binds to HSPGs, on the interaction between VEGF165 and HS and angiogenesis. Mice with tg2 deficiency showed transiently enhanced retina vessel formation and increased vascularization of VEGF165-containing Matrigel implants. In addition, endothelial cells in which TG2 was knocked down exhibited enhanced VEGF165-induced sprouting and migration, which was associated with increased phosphorylation of VEGFR2 at Tyr(951) and its targets Src and Akt. TG2 knockdown did not affect the phosphorylation of VEGFR2 at Tyr(1175) or cell proliferation in response to VEGF165 and sprouting or signaling in response to VEGF121. Decreased phosphorylation of VEGFR2 at Tyr(951) was due to ECM-localized TG2, which reduced the binding of VEGF165 to endothelial ECM in a manner that required its ability to bind to HS but not its catalytic activity. Surface plasmon resonance assays demonstrated that TG2 impeded the interaction between VEGF165 and HS. These results show that TG2 controls the formation of VEGF165-HSPG complexes and suggest that this regulation could be pharmacologically targeted to modulate developmental and therapeutic angiogenesis

Published
2015
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9. Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke

Author

Corinne Ardidie-Robouant, Mikael Mazighi, Elodie Berland, Bérard Coqueran, Andrew J. Murphy, George D. Yancopoulos, Bertrand Lapergue, Mathieu Lesage, Claire Bouleti, Charles Duyckaerts, David M. Valenzuela, Stéphane Germain, Isabelle Margaill, Daniel Henrion, Gavin Thurston, Gilles Kauffenstein, Catherine Monnot, Jean Michel Serfaty, Thomas Mathivet, Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre interdisciplinaire de recherche en biologie (CIRB), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL)

Subjects
Male, Vascular Endothelial Growth Factor A, Pathology, Cell Membrane Permeability, Angiogenesis, Brain Edema, Pharmacology, Ischaemia, Inbred C57BL, Brain Ischemia, angiogenesis, Mice, 0302 clinical medicine, ANGPTL4, Hypoxia, Nootropic Agents, 0303 health sciences, Brain, Cadherins, Stroke, Vascular endothelial growth factor A, medicine.anatomical_structure, src-Family Kinases, Blood-Brain Barrier, Encephalitis, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Endothelium, Ischemia, Brain damage, Adherens junction, Angiopoietin, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Vascular, medicine, Angiopoietin-Like Protein 4, Animals, Humans, 030304 developmental biology, business.industry, Acute cerebral infarction, Endothelial Cells, vascular biology, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Mice, Inbred C57BL, Endothelium, Vascular, business, Angiopoietins, 030217 neurology & neurosurgery
Abstract

Aims Given the impact of vascular injuries and oedema on brain damage caused during stroke, vascular protection represents a major medical need. We hypothesized that angiopoietin-like 4 (ANGPTL4), a regulator of endothelial barrier integrity, might exert a protective effect during ischaemic stroke. Methods and results Using a murine transient ischaemic stroke model, treatment with recombinant ANGPTL4 led to significantly decreased infarct size and improved behaviour. Quantitative characteristics of the vascular network (density and branchpoints) were preserved in ANGPTL4-treated mice. Integrity of tight and adherens junctions was also quantified and ANGPTL4-treated mice displayed increased VE-cadherin and claudin-5-positive areas. Brain oedema was thus significantly decreased in ANGPTL4-treated mice. In accordance, vascular damage and infarct severity were increased in angptl4 -deficient mice thus providing genetic evidence that ANGPTL4 preserves brain tissue from ischaemia-induced alterations. Altogether, these data show that ANGPTL4 protects not only the global vascular network, but also interendothelial junctions and controls both deleterious inflammatory response and oedema. Mechanistically, ANGPTL4 counteracted VEGF signalling and thereby diminished Src-signalling downstream from VEGFR2. This led to decreased VEGFR2–VE-cadherin complex disruption, increased stability of junctions and thus increased endothelial cell barrier integrity of the cerebral microcirculation. In addition, ANGPTL4 prevented neuronal loss in the ischaemic area. Conclusion These results, therefore, show ANGPTL4 counteracts the loss of vascular integrity in ischaemic stroke, by restricting Src kinase signalling downstream from VEGFR2. ANGPTL4 treatment thus reduces oedema, infarct size, neuronal loss, and improves mice behaviour. These results suggest that ANGPTL4 constitutes a relevant target for vasculoprotection and cerebral protection during stroke.

Published
2013
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