Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α

Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1 alpha(-/-) embryonic stem cells that did not express the O-2-regulated HIF-1 alpha subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1 alpha(-/-) embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1 alpha resulted in developmental arrest and lethality by E11 of Hif1 alpha(-/-) embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1 alpha(+/+) embryos, HIF-1 alpha expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1 alpha(-/-)embryos. These results demonstrate that HIF-1 alpha is a master regulator of cellular and developmental O-2 homeostasis.