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Blood, 15 January 2006, Vol. 107, No. 2, pp. 584-590.
Prepublished online as a Blood First Edition Paper on September 27, 2005; DOI 10.1182/blood-2005-07-3033.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Inhibition of hypoxia-inducible factor activity in endothelial cells disrupts embryonic cardiovascular development
Alexander H. Licht,
Felix Müller-Holtkamp,
Ingo Flamme, and
Georg Breier
From the Department of Pathology, Faculty of Medicine, University of Technology, Dresden, Germany; Department of Molecular Cell Biology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; and Bayer Health Care, Wuppertal, Germany.
Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen levels. By stimulating the expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), they trigger the neovascularization of tissues under physiologic and pathologic conditions. Here, we have investigated the endothelial cell–autonomous HIF function in blood vessel growth and development by expressing a dominant-negative HIF mutant (HIFdn) that inhibits the transcriptional responses mediated by both HIF-1 and HIF-2, specifically in endothelial cells of transgenic mice. HIFdn transgenic embryos were growth retarded and died around E11.5. Primitive vascular networks were established, but vascular remodeling in the yolk sac and in the embryo proper was defective, and vascular sprouts failed to invade the neuroepithelium. In addition, heart looping was incomplete, and the ventricles of the heart were thin-walled and lacked trabeculation. Similar cardiovascular defects have been observed in Tie2–deficient mouse embryos. Consistently, HIFdn transgenic embryos expressed reduced levels of the endothelial angiopoietin receptor, Tie-2, whereas other endothelial markers, such as PECAM-1, Tie-1, and VE-cadherin were not affected. These results show that HIFs in endothelial cells are essential for embryonic heart and blood vessel development and control angiogenesis and vascular remodeling.
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