Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α
- Narayan V. Iyer1,5,
- Lori E. Kotch1,5,
- Faton Agani1,
- Sandra W. Leung1,
- Erik Laughner1,
- Roland H. Wenger2,
- Max Gassmann2,
- John D. Gearhart3,
- Ann M. Lawler3,
- Aimee Y. Yu1, and
- Gregg L. Semenza1,4
- 1Center for Medical Genetics, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3914 USA; 2Institute of Physiology, University of Zurich-Irchel, 8057 Zurich, Switzerland; 3Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 USA
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 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.