Regulation of gene expression by HIF-1.

Hypoxia-inducible factor 1 (HIF-1) is a critical mediator of physiological responses to acute and chronic hypoxia. First, HIF-1 is required for the development of the systems that mediate these responses, including the heart, blood and blood vessels. Mice with complete HIF-1alpha deficiency manifest developmental defects that involve all three components of the circulatory system. Second, HIF-1 mediates changes in gene expression that underlie physiological responses to chronic hypoxia, such as increased erythropoiesis and angiogenesis. Hif1a(+/-) mice, which are partially HIF-1alpha deficient, manifest impaired hypoxia-induced pulmonary vascular remodelling. Smooth muscle cells from pulmonary arteries (PASMCs) of wild-type mice subjected to chronic hypoxia manifest hypertrophy, depolarization, increased [Ca2+]i, and decreased voltage-gated K+ currents. These responses are impaired in PASMCs from Hif1a(+/-) mice. Carotid bodies isolated from Hif1a(+/-) mice are unresponsive to hypoxia despite normal histology and normal responses to cyanide stimulation. Rat PC12 cells share properties with O2-sensing glomus cells of the carotid body, including hypoxia-inducible expression of tyrosine hydroxylase, the rate limiting enzyme for catecholamine biosynthesis. In PC12 cells subjected to intermittent hypoxia, Ca2+/calmodulin-dependent kinase activity leads to HIF-1 transcriptional activity and tyrosine hydroxylase mRNA expression. Thus, HIF-1 regulates both acute and chronic responses to continuous and intermittent hypoxia.