Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology.
Hypoxia-inducible factor (HIF)-1 is a transcription factor that is activated in response to hypoxia and growth factor/cytokine signaling via regulation of the HIF-1alpha subunit. HIF-1 has been implicated in the pathogenesis of pulmonary hypertension based on both experimental and clinical data. In a mouse model of pulmonary hypertension, hypoxia-induced increases in right ventricular mass, right ventricular pressure, and medial wall thickness of pulmonary arterioles were impaired in mice that were heterozygous for a null allele at the locus encoding HIF-1alpha compared to wild-type littermates. Electrophysiologic analyses revealed that the hypoxia-induced hypertrophy and depolarization of pulmonary arterial smooth muscle cells from wild-type mice was significantly impaired in heterozygotes. In clinical studies, immunohistochemical analyses of plexiform lesions within the lungs of patients with severe pulmonary hypertension revealed dramatic overexpression of HIF-1alpha within proliferating endothelial cells. These cells also expressed vascular endothelial growth factor (VEGF), which is the product of a known HIF-1 target gene, indicating that autocrine VEGF-VEGF receptor signaling may contribution to the pathogenesis of plexiform lesions. These studies implicate HIF-1 in pathophysiologic alterations of both smooth muscle and endothelial cell biology in patients with pulmonary hypertension.
Semenza
Gregg L
GL
The Johns Hopkins University School of Medicine, Baltimore, MD, USA. gsemenza@jhmi.edu
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A