Published Online
on April 25, 2005

A more recent version of this article appeared on May 3, 2005

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Submitted on May 17, 2004
Revised on December 11, 2004
Accepted on December 17, 2004

Endothelium-Intrinsic Requirement for Hif-2 During Vascular Development

Li-Juan Duan MSc, Yahui Zhang-Benoit MSc, and Guo-Hua Fong PhD^*

From the Center for Vascular Biology, Departments of Cell Biology and Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Conn.

^* To whom correspondence should be addressed. E-mail: fong{at}nso2.uchc.edu.

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-2 (Hif-2, 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 cDNA in the vascular endothelium of Hif-2^-/- embryos by an embryonic stem (ES) cell-mediated transgenic approach and assessed whether endothelium-specific reexpression of Hif-2 could rescue vascular development. Here we report that although ES cell-derived Hif-2^-/- embryos developed severe vascular defects by embryonic day (E) 11.5 and died in utero before E12.5, endothelium-specific expression of Hif-2 cDNA restored normal vascular development at all stages examined (up to E14.5) and allowed Hif-2^-/- embryos to survive at a frequency comparable to that of Hif-2^+/- embryos. Furthermore, we found that Tie-2 expression was significantly reduced in Hif-2^-/- mutants but was restored by Hif-2 cDNA expression.

Conclusions--These data demonstrate an intrinsic requirement for Hif-2 by endothelial cells and imply that hypoxia may control endothelial functions directly via Hif-2-regulated Tie-2 expression.

Key words: angiogenesis • morphogenesis • hypoxia • endothelium

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