Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1

Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS domain transcription factor that mediates changes in gene expression in response to changes in O2 concentration. Genes that are transcriptionally activated by HIF-1 in hypoxic cells encode proteins that increase O2 delivery or allow metabolic adaptation to limited O2 availability. HIF-1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF-1 and VEGF. Expression of HIF-1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O2-regulated HIF-1 alpha subunit. Mouse embryos lacking HIF-1 alpha expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF-1 functions as a master regulator of O2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.