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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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Submitted July 28, 2005
Accepted September 12, 2005
Inhibition of hypoxia-inducible factor activity in endothelial cells disrupts embryonic cardiovascular development
Alexander H Licht, Felix Muller-Holtkamp, Ingo Flamme, and Georg Breier*
Department of Pathology, Faculty of Medicine, University of Technology, Dresden, Germany
Department of Molecular Cell Biology, Max Planck Institute for Physiological and Clinical Research, Bad Nauheim, Germany
Bayer Health Care, Wuppertal, Germany
* Corresponding author; email: georg.breier{at}uniklinikum-dresden.de.
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 physiological and pathological 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 Tie-2 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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