title: ANGPTL4-αvβ3 interaction counteracts hypoxia-induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2.
abstract: Dynamic control of endothelial cell junctions is essential for vascular homeostasis and angiogenesis. We recently provided genetic evidence that ANGPTL4 is a key regulator of vascular integrity both during developmental and in hypoxia-induced pathological conditions. The purpose of the present study was to decipher the molecular mechanisms through which ANGPTL4 regulates vascular integrity. Using surface plasmon resonance and proximity ligation assays, we show that ANGPTL4 binds integrin αvβ3. In vitro and in vivo functional assays with Angptl4-deficient mice demonstrate that ANGPTL4-αvβ3 interaction is necessary to mediate ANGPTL4 vasoprotective effects. Mechanistically, ANGPTL4-αvβ3 interaction enhances Src recruitment to integrin αvβ3 and inhibits Src signalling downstream of vascular endothelial growth factor receptor 2 (VEFGR2), thereby repressing hypoxia-induced breakdown of VEGFR2-VE-cadherin and VEGFR2-αvβ3 complexes. We further demonstrate that intravitreal injection of recombinant human ANGPTL4 limits vascular permeability and leads to increased adherens junction and tight junction integrity. These findings identify a novel mechanism by which ANGPTL4 counteracts hypoxia-driven vascular permeability through integrin αvβ3 binding, modulation of VEGFR2-Src kinase signalling, and endothelial junction stabilization. We further demonstrate that Angptl4-deficient mice show increased vascular leakage in vivo in a model of laser-induced choroidal neovascularization, indicating that this newly identified ANGPTL4-αvβ3 axis might be a target for pharmaceutical intervention in pathological conditions. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.|Ecole Doctorale 394: Physiologie, Physiopathologie et Thérapeutique, Université Pierre et Marie Curie, Paris, France.
authors: Elisa
authors: E
authors: Gomez Perdiguero
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.|Ecole Doctorale 394: Physiologie, Physiopathologie et Thérapeutique, Université Pierre et Marie Curie, Paris, France.
authors: Athanasia
authors: A
authors: Liabotis-Fontugne
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.
authors: Mélanie
authors: M
authors: Durand
authors: UMR 5086 CNRS Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors: Clément
authors: C
authors: Faye
authors: UMR 5086 CNRS Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors: Sylvie
authors: S
authors: Ricard-Blum
authors: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.
authors: Manuel
authors: M
authors: Simonutti
authors: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.
authors: Sébastien
authors: S
authors: Augustin
authors: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.
authors: Bryan M
authors: BM
authors: Robb
authors: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.|Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France.
authors: Michel
authors: M
authors: Paques
authors: Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
authors: David M
authors: DM
authors: Valenzuela
authors: Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
authors: Andrew J
authors: AJ
authors: Murphy
authors: Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
authors: George D
authors: GD
authors: Yancopoulos
authors: Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
authors: Gavin
authors: G
authors: Thurston
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.
authors: Ariane
authors: A
authors: Galaup
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.
authors: Catherine
authors: C
authors: Monnot
authors: Centre for Interdisciplinary Research in Biology (CIRB), College de France, CNRS, INSERM, PSL Research University, Paris, France.
authors: Stéphane
authors: S
authors: Germain
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D012160:Retina / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D039302:Integrin alphaVbeta3; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases
keywords: VE-cadherin; VEGFR2; angiopoietin-like 4; hypoxia; integrin αvβ3; vascular permeability