von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina
Open Access
- 1 May 2010
- journal article
- Published by The Company of Biologists in Development
- Vol. 137 (9), 1563-1571
- https://doi.org/10.1242/dev.049015
Abstract
In early neonates, the fetal circulatory system undergoes dramatic transition to the adult circulatory system. Normally, embryonic connecting vessels, such as the ductus arteriosus and the foramen ovale, close and regress. In the neonatal retina, hyaloid vessels maintaining blood flow in the embryonic retina regress, and retinal vessels take over to form the adult-type circulatory system. This process is regulated by a programmed cell death switch mediated by macrophages via Wnt and angiopoietin 2 pathways. In this study, we seek other mechanisms that regulate this process, and focus on the dramatic change in oxygen environment at the point of birth. The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor αs (HIF-αs) under normoxic, but not hypoxic, conditions. To examine the role of oxygen-sensing mechanisms in retinal circulatory system transition, we generated retina-specific conditional-knockout mice for VHL (Vhlα-CreKO mice). These mice exhibit arrested transition from the fetal to the adult circulatory system, persistence of hyaloid vessels and poorly formed retinal vessels. These defects are suppressed by intraocular injection of FLT1-Fc protein [a vascular endothelial growth factor (VEGF) receptor-1 (FLT1)/Fc chimeric protein that can bind VEGF and inhibit its activity], or by inactivating the HIF-1α gene. Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina.This publication has 44 references indexed in Scilit:
- Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathyProceedings of the National Academy of Sciences of the United States of America, 2008
- Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and PhotoreceptorsPLOS ONE, 2008
- Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in miceJCI Insight, 2008
- Erythropoietin deficiency decreases vascular stability in miceJCI Insight, 2008
- Obligatory participation of macrophages in an angiopoietin 2-mediated cell death switchDevelopment, 2007
- Neovascular glaucomaProgress in Retinal and Eye Research, 2007
- Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivoJCI Insight, 2007
- SOCS3 is required to temporally fine-tune photoreceptor cell differentiationDevelopmental Biology, 2007
- Acute postnatal ablation of Hif-2 α results in anemiaProceedings of the National Academy of Sciences of the United States of America, 2007
- Neuroprotective Effects of Angiotensin II Type 1 Receptor (AT1R) Blocker, Telmisartan, via Modulating AT1R and AT2R Signaling in Retinal InflammationInvestigative Ophthalmology & Visual Science, 2006