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ANGPTL4 –αvβ3 interaction counteracts hypoxia‐induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2
Author(s) -
Gomez Perdiguero Elisa,
LiabotisFontugne Athanasia,
Durand Mélanie,
Faye Clément,
RicardBlum Sylvie,
Simonutti Manuel,
Augustin Sébastien,
Robb Bryan M,
Paques Michel,
Valenzuela David M,
Murphy Andrew J,
Yancopoulos George D,
Thurston Gavin,
Galaup Ariane,
Monnot Catherine,
Germain Stéphane
Publication year - 2016
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4805
Subject(s) - microbiology and biotechnology , vascular permeability , proto oncogene tyrosine protein kinase src , angptl4 , vascular endothelial growth factor , angiogenesis , adherens junction , ve cadherin , sprouting angiogenesis , kinase insert domain receptor , integrin , biology , cancer research , signal transduction , receptor , chemistry , vascular endothelial growth factor a , endothelial stem cell , cadherin , neovascularization , endocrinology , biochemistry , in vitro , cell , vegf receptors , gene
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.