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

Narayan V. Iyer, Lori E. Kotch, Faton Agani, Sandra W. Leung, Erik Laughner, Roland H. Wenger, Max Gassmann, John D. Gearhart, Ann M. Lawler, Aimee Y. Yu, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)149-162
Number of pages14
JournalGenes and Development
Volume12
Issue number2
DOIs
StatePublished - Jan 15 1998

Keywords

  • Cardiovascular development
  • Glycolysis
  • Knockout
  • Oxygen
  • VEGF

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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