Cellular and developmental control of O 2 homeostasis by hypoxia-inducible factor 1α

• Published in: Genes & development 1998-01, Vol.12 (2), p.149-162
• Main Authors: Iyer, Narayan V., Kotch, Lori E., Agani, Faton, Leung, Sandra W., Laughner, Erik, Wenger, Roland H., Gassmann, Max, Gearhart, John D., Lawler, Ann M., Yu, Aimee Y., Semenza, Gregg L.
• Format: Article
• Language: English
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.12.2.149

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 O 2 -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 O 2 homeostasis.