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Involvement of Hypoxia-Inducible Factor 1 in Pulmonary Pathophysiology^*

^* From The Johns Hopkins University School of Medicine, Baltimore, MD.

Correspondence to: Gregg L. Semenza, MD, PhD, 733 North Broadway, Suite 671, Baltimore, MD 21205; e-mail: gsemenza{at}jhmi.edu

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-1 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-1 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-1 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.

Key Words: gene expression • hypoxia • pulmonary hypertension

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