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

NV Iyer, LE Kotch, F Agani, SW Leung… - Genes & …, 1998 - genesdev.cshlp.org
NV Iyer, LE Kotch, F Agani, SW Leung, E Laughner, RH Wenger, M Gassmann, JD Gearhart…
Genes & development, 1998genesdev.cshlp.org
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 …
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 hypoxicHif1a −/− embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1α resulted in developmental arrest and lethality by E11 ofHif1a −/− embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. InHif1a +/+ embryos, HIF-1α expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death inHif1a −/− embryos. These results demonstrate that HIF-1α is a master regulator of cellular and developmental O2 homeostasis.
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