VEGF164 is required for ischemia–induced retinal neovascularization in mice

Abstract

Abstract: : Purpose: The pathological and physiological development of retinal vasculature is controlled in large part by vascular endothelial growth factor (VEGF). Previous work from our laboratory has demonstrated that ischemia–induced retinal neovascularization is caused in part by a local inflammatory response. Since the VEGF164 isoform has an enhanced capacity to trigger pro–inflammatory events, we characterized its role in hypoxia–induced neovascularization using VEGF164–deficient (VEGF120/188) mice. Methods: VEGF120/188 mice were generated by mating VEGF+/120 male mice with VEGF+/188 female mice, both of which were produced via targeted mutagenesis with Cre/lox P–mediated site–specific recombination in embryonic stem cells. Retinopathy of prematurity was induced by exposing 7–day–old mice to 75% oxygen for 5 days followed by 5 days in room air. The pathological and physiological development of retinal vessels was evaluated by PECAM–1, immunostaining of retinal whole mounts and serial sections. Results: VEGF120/188 mice under normoxic conditions exhibited the same development of the retinal vasculature as age–matched wild–type mice. After 5 days of hyperoxia, there was no difference in the avascular region (i.e., vascular obliteration) between transgenic and wild–type mice. However, pathological neovascularization following return to normoxic conditions (relative hypoxia) was suppressed by over 90% in the VEGF120/188 mice. Conclusions: Our data demonstrate that the combination of the VEGF120 and VEGF188 isoforms alone are sufficient to drive physiological retinal vessel growth, but VEGF164 is required for pathological retinal neovascularization.

Keywords: retinopathy of prematurity • retinal neovascularization • pathology: experimental