von Hippel Lindau Protein and Hypoxia Inducible Factor-2alpha Degradation in Astrocytes is Essential for Regression of the Hyaloidal Vasculature

Abstract

Purpose: : Regression of the hyaloidal vasculature is a physiological process that signals the transition from embryonic to adult circulation in the retina. Recently, we found that molecular oxygen-sensing such as von Hippel Lindau Protein (VHL) and hypoxia-inducible factors (HIFs) in retinal neurons are required for this transition (Kurihara et al. Development 2010). In this study, we explored the contribution of VHL/HIF signaling in other cell types in the retina to this process.

Methods: : Transgenic mice expressing Cre recombinase specifically in astrocytes (GFAP-Cre mice), were mated with VHL^{floxed/floxed} mice, HIF-1a^{floxed/floxed} mice HIF-2a^{floxed/floxed} mice and/or VEGF^{floxed/floxed} mice to generate astrocyte-specific oxygen-sensing gene conditional knockout mice.

Results: : We demonstrate that a deficiency in degradation of HIFs by deletion of VHL is associated with accelerated hyaloidal vessel regression compared to wild type littermates in early neonatal stages despite upregulation of VEGF in the retina. After postnatal day 14, however, these mice exhibit massive secondary growth of hyaloidal vessels along the surface of the posterior lens capsule. Genetic deletion of HIF-2a or VEGF, but not HIF-1a, rescues the vascular phenotypes in the VHL; GFAP-Cre KO mice.

Conclusions: : These data suggest that the VHL/HIF-2a/VEGF pathway in astrocytes regulates the normal regression of the hyaloidal vasculature.

Keywords: astrocyte • hypoxia • retinal development