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(Circulation. 2005;111:2227-2232.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Endothelium-Intrinsic Requirement for Hif-2 During Vascular Development

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

Reprint requests to Guo-Hua Fong, PhD, Center for Vascular Biology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-3501. E-mail fong{at}nso2.uchc.edu

Received May 17, 2004; revision received December 11, 2004; accepted December 17, 2004.

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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