Endothelium-intrinsic requirement for Hif-2alpha during vascular development.
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-2alpha (Hif-2alpha, 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.


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


CONCLUSIONS
These data demonstrate an intrinsic requirement for Hif-2alpha by endothelial cells and imply that hypoxia may control endothelial functions directly via Hif-2alpha-regulated Tie-2 expression.
Duan
Li-Juan
LJ
Center for Vascular Biology, Department of Cell Biology and Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Conn 06030-3501, USA.
Zhang-Benoit
Yahui
Y
Fong
Guo-Hua
GH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian / Q000098:blood supply; D004730:Endothelium, Vascular / Q000254:growth & development* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D000860:Hypoxia; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D042787:Receptor, TIE-2 / Q000235:genetics / Q000502:physiology; D033581:Stem Cell Transplantation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D042787:Receptor, TIE-2; D000099162:Endothelial PAS Domain-Containing Protein 1