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 Hif1a(-/-) embryonic stem cells that did not express the O₂-regulated HIF-1α 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 Hif1a(-/-) embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF- 1α resulted in developmental arrest and lethality by E11 of Hif1a(-/-) embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a(+/+) embryos, HIF-1α expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a(-/-) embryos. These results demonstrate that HIF-1α is a master regulator of cellular and developmental O₂ homeostasis.