Hypoxia-mediated pulmonary vasoconstriction (HPV) and vascular medial hypertrophy are major causes for the elevated pulmonary vascular resistance and arterial pressure in patients with pulmonary arterial hypertension (PAH). A rise in cytoplasmic calcium in pulmonary artery smooth muscle cells (PASMC) is a major trigger for PASMC contraction and an important stimulus for PASMC proliferation. A rise in cytosolic calcium in PASMC and PA endothelial cells (PAEC) can also serve as a signal to stimulate gene expression of mitogens. Hypoxia selectively inhibits voltage-gated potassium (Kv) channels (e.g., Kv1.5) in PASMC, causing membrane depolarization and opening of voltage-dependent calcium channels, a unique mechanism involved in inducing acute HPV. Hypoxia also increases cytoplasmic calcium and enhances AP-1 DMA binding activity in PAEC by selectively upregulating transient receptor potential (TRPC) channel (e.g., TRPC4) expression, which subsequently upregulates AP-1 responsive genes. This data indicates that downregulated Kv channels in PASMC and upregulated TRPC channels in PAEC are in part involved in hypoxia-mediated pulmonary vasoconstriction and vascular remodeling (via stimulating PASMC growth). Based on this data, we hypothesize that i) acute hypoxia-induced functional inhibition of Kv channels is a unique and intrinsic mechanism in PASMC to increase cytoplasmic calcium and cause HPV, and ii) chronic hypoxia-mediated downregulation of Kv channel expression in PASMC and upregulation of TRPC4 channel expression in PAEC both contribute to stimulating PASMC proliferation and pulmonary vascular medial hypertrophy. We propose 3 specific aims to test the hypothesis: 1) to define which and how Kv channel subunits are selectively inhibited by acute hypoxia in PASMC, 2) to define the mechanisms involved in chronic hypoxia-induced inhibition of Kv channel gene expression, and 3) to examine how chronic hypoxia upregulates TRPC channels and enhances AP-1 binding activity in PAEC.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RES-B (02))
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Denholm, Elizabeth M
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
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