CELLULAR AND DEVELOPMENTAL CONTROL OF O-2 HOMEOSTASIS BY HYPOXIA-INDUCIBLE FACTOR 1-ALPHA

Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, strok e, and other major causes of mortality. Hypoxia inducible factor 1 (HI F-1) is the only known mammalian transcription factor expressed unique ly in response to physiologically relevant levels of hypoxia. We now r eport that in Hif1 alpha(-/-) embryonic stem cells that did not expres s the O-2-regulated HIF-1 alpha subunit, levels of mRNAs encoding gluc ose transporters and glycolytic enzymes were reduced, and cellular pro liferation was impaired. Vascular endothelial growth factor mRNA expre ssion was also markedly decreased in hypoxic Hif1 alpha(-/-) embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1 a lpha resulted in developmental arrest and lethality by E11 of Hif1 alp ha(-/-) embryos that manifested neural tube defects, cardiovascular ma lformations, 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 homeost asis.