Vasohibin is Up‐regulated by VEGF in the Retina and Suppresses VEGF receptor 2 and Retinal Neovascularization

Abstract

Vasohibin is a recently identified protein that is up-regulated in cultured vascular endothelial cells by VEGF and FGF2. It inhibits endothelial cell migration, proliferation, and tube formation, and suppresses angiogenesis. This has led to the hypothesis that vasohibin functions as a negative feedback inhibitor of angiogenesis. We tested that hypothesis in a well-characterized model of retinal neovascularization. In ischemic retina, increased expression of VEGF was accompanied by elevation of vasohibin mRNA and blocking of the increase in vegf mRNA with vegf siRNA significantly attenuated the rise in vasohibin mRNA. In Rho/VEGF transgenic mice, there was also a significant increase in vasohibin mRNA in retinas. Endogenous vasohibin expression was colocalized with PECAM. Intraocular injection of recombinant vasohibin or AdVasohibin strongly suppressed retinal neovascularization in mice with ischemic retinopathy. Knockdown of vasohibin mRNA, had no significant effect on VEGF or VEGFR1 mRNA levels, but caused a significant elevation in the level of VEGFR2 mRNA, more retinal neovascularization formation. These data support the hypothesis that vasohibin acts as a negative feedback regulator of neovascularization in the retina, and suggest that suppression of VEGFR2 may play some role in mediating its activity.