Hypoxia is a potent inducer of angiogenesis during which endothelial cells (ECs) undergo modulations of cell-cell and cell-matrix interactions. ANGPTL4 expression is induced by hypoxia in ECs (1,2) and interacts with the extracellular matrix (3) modulating ECs adhesion, migration and sprouting through cytoskeleton reorganisation (4).
Analyse whether in vivo ANGPTL4 plays a role in modulating hypoxia-driven angiogenesis in the retina, both in development and in vascular retinal pathologies.
C57/Bl6 angptl4 KO mice and WT littermates were used. An hyperoxia chamber was used to establish the oxygen-induced retinopathy (OIR). Mice were exposed to 75 % oxygen from P7 to P12 leading to retinal vessel loss. After returning to room air, hypoxia induces neovascularisation, evaluated at P17 when greatest.
Developmental angiogenesis of the retina in P5-P7 pups was analysed. Angptl4 is expressed by ECs and angptl4 -/- retinas show a decreased number of branchpoints (p<0,005) as well as an increased vascular density (p<0,001). Angptl4 -/- veins were dilated compared to angptl4+/- (p<0,001). Altogether, loss of angptl4 expression in the developing retina lead to an immature vascular plexus. Moreover, angptl4 -/- retinas showed an increased basal vascular leakage (p<0,0,05). Confocal analysis also showed that pericyte coverage might be involved.
We also show that ANGPTL4 is expressed during OIR by ECs. Retinal wholemount preparations stained with isolectin B4 were performed. At P12, the retinal vaso-obliterated area was not affected in angptl4 -/- mice, suggesting that ANGPTL4 has no effect in the hyperoxia-induced vaso-obliteration. In contrast, the neovascular angiogenic response was significantly alteredin angptl4 -/- mice at P17 (p<0,001). Thus, ANGPTL4 is essential for regulating the growth of new retinal vessels in an ischemic environment.
Altogether, this data demonstrate that ANGPTL4 plays a critical role in hypoxia-induced angiogenesis, both in developmental and pathological conditions, by affecting 1) vascular density, 2) basal vascular permeability, and 3) pericyte coverage.
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(2)Galaup A, Proc Natl Acad Sci U S A. 2006
(3)Cazes A, Circ Res. 2006
(4)Chomel C, FASEB J. 2008Le texte complet de cet article est disponible en PDF.