Endothelium-Intrinsic Requirement for Hif-2 α During Vascular Development

Abstract

Background— The development of the vascular system is a complex process that involves communications among multiple cell types. As such, it is important to understand whether a specific gene regulates vascular development directly from within the vascular system or indirectly from nonvascular cells. Hypoxia-inducible factor-2α (Hif-2α, or endothelial PAS protein-1 [EPAS-1]) is required for vascular development in mice, but it is not clear whether its requirement resides directly in endothelial cells. Methods and Results— To address this issue, we expressed Hif-2 α cDNA in the vascular endothelium of Hif-2 α −/− embryos by an embryonic stem (ES) cell–mediated transgenic approach and assessed whether endothelium-specific reexpression of Hif-2 α could rescue vascular development. Here we report that although ES cell–derived Hif-2 α −/− embryos developed severe vascular defects by embryonic day (E) 11.5 and died in utero before E12.5, endothelium-specific expression of Hif-2 α cDNA restored normal vascular development at all stages examined (up to E14.5) and allowed Hif-2 α −/− embryos to survive at a frequency comparable to that of Hif-2 α +/− embryos. Furthermore, we found that Tie-2 expression was significantly reduced in Hif-2 α −/− mutants but was restored by Hif-2 α cDNA expression. Conclusions— These data demonstrate an intrinsic requirement for Hif-2α by endothelial cells and imply that hypoxia may control endothelial functions directly via Hif-2α–regulated Tie-2 expression.