ANGPTL4-αvβ3 interaction counteracts hypoxia-induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2

Elisa Gomez Perdiguero , Athanasia Liabotis-Fontugne , Mélanie Durand , Clément Faye , Sylvie Ricard-Blum , Manuel Simonutti , Sébastien Augustin , Bryan M. Robb , Michel Paques , David M. Valenzuela , Andrew J. Murphy , George D. Yancopoulos , Gavin Thurston , Ariane Galaup , Catherine Monnot , Stéphane Germain (1, 2, 3)

1 Angiogénèse embryonnaire et pathologique
2 CIRB - Centre interdisciplinaire de recherche en biologie
3 INSERM U36 - Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale

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 v3. In vitro and in vivo functional assays with Angptl4-deficient mice demonstrate that ANGPTL4-v3 interaction is necessary to mediate ANGPTL4 vasoprotective effects. Mechanistically, ANGPTL4-v3 interaction enhances Src recruitment to integrin v3 and inhibits Src signalling downstream of vascular endothelial growth factor receptor 2 (VEFGR2), thereby repressing hypoxia-induced breakdown of VEGFR2-VE-cadherin and VEGFR2-v3 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 v3 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-v3 axis might be a target for pharmaceutical intervention in pathological conditions.

Keywords: hypoxia vascular permeability angiopoietin-like 4 VEGFR2 integrin αvβ3 VE-cadherin; hypoxia; vascular permeability; angiopoietin-like 4; VEGFR2; integrin αvβ3; VE-cadherin

Domains: Life Sciences [q-bio]

Elisa Gomez Perdiguero, Athanasia Liabotis-Fontugne, Mélanie Durand, Clément Faye, Sylvie Ricard-Blum, et al.. ANGPTL4-αvβ3 interaction counteracts hypoxia-induced vascular permeability by modulating Src signalling downstream of vascular endothelial growth factor receptor 2. Journal of Pathology, 2016, 240, pp.461 - 471. ⟨10.1002/path.4805⟩. ⟨hal-02142760⟩