von Hippel-Lindau Tumor Suppressor Protein Is Required for Transition From Embryonic to Adult Circulatory System in Retina

Abstract

Purpose: : Although von Hippel-Lindau tumor suppressor protein (pVHL) / hypoxia-inducible factor-s (HIF-s) pathway in molecular oxygen sensing is well known, its role in normal tissue development is poorly understood, especially at the change of oxygen concentration as observed at the time of birth. In this study, utilizing retina-specific conditional knockout technology, we explored the precise in vivo function of VHL and HIF-1 in retinal vascular development.

Methods: : Transgenic mice expressing Cre recombinase specifically in retina (-Cre mice), were mated with VHL^{floxed/floxed} mice, or HIF-1^{floxed/floxed} mice to generate retina-specific conditional knockout mice for VHL (VHL^{-Cre KO} mice) or HIF-1. To determine the role of vascular endothelial growth factor (VEGF), we injected a potent VEGF inhibitor, Flt1-Fc chimeric protein

Results: : VHL^{-Cre KO} mice exhibited collateral flow from hyaloid vessels into retinal vessels, poorly-formed retinal vessels, and persistent hyaloid vessels in the stage when wild-type mice complete the transition from fetal to adult circulation. These vascular defects in VHL^{-Cre KO} mice were suppressed by intraocular injection of Flt1-Fc chimeric protein or gene inactivation of HIF-1 concomitantly (HIF-1; VHL^{-Cre KO}).

Keywords: retinal development • retinal neovascularization • transcription factors