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(Circulation Research. 2006;98:1528.)
© 2006 American Heart Association, Inc.

Cellular Biology

Hypoxia Inducible Factor 1 Mediates Hypoxia-Induced TRPC Expression and Elevated Intracellular Ca²⁺ in Pulmonary Arterial Smooth Muscle Cells

Jian Wang, Letitia Weigand, Wenju Lu, J.T. Sylvester, Gregg L. Semenza, Larissa A. Shimoda

From the Division of Pulmonary and Critical Care Medicine (J.W., L.W., W.L., J.T.S., L.A.S.); Vascular Biology Program (G.L.S.), Institute for Cell Engineering; Departments of Medicine (J.W., L.W., W.L., J.T.S., G.L.S., L.A.S.), Pediatrics (G.L.S.), Oncology (G.L.S.), and Radiation Oncology (G.L.S.); and McKusick–Nathans Institute of Genetic Medicine (G.L.S.), The Johns Hopkins University School of Medicine, Baltimore, Md.

Correspondence to Larissa A. Shimoda, PhD, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, JHAAC 4B.82B, Baltimore, MD 21224. E-mail shimodal{at}welch.jhu.edu

Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca²⁺ concentration ([Ca²⁺]_i) was elevated in PASMCs from chronically hypoxic rats because of Ca²⁺ influx through pathways other than L-type Ca²⁺ channels and that development of hypoxic pulmonary hypertension required full expression of the transcription factor hypoxia inducible factor 1 (HIF-1). In this study, we examined the effect of CH on the activity and expression of store-operated Ca²⁺ channels (SOCCs) and the regulation of these channels by HIF-1. Capacitative Ca²⁺ entry (CCE) was enhanced in PASMCs from intrapulmonary arteries of rats exposed to CH (10% O₂; 21 days), and exposure to Ca²⁺-free extracellular solution or SOCC antagonists (SKF96365 or NiCl₂) decreased resting [Ca²⁺]_i in these cells. Expression of TRPC1 and TRPC6, but not TRPC4, mRNA and protein was increased in PASMCs from rats and wild-type mice exposed to CH, in PASMCs from normoxic animals cultured under hypoxic conditions (4% O₂; 60 hours), and in PASMCs in which HIF-1 was overexpressed under nonhypoxic conditions. Hypoxia-induced increases in basal [Ca²⁺]_i and TRPC expression were absent in mice partially deficient for HIF-1. These results suggest that increased TRPC expression, leading to enhanced CCE through SOCCs, may contribute to hypoxic pulmonary hypertension by facilitating Ca²⁺ influx and increasing basal [Ca²⁺]_i in PASMCs and that this response is mediated by HIF-1.

Key Words: Ca²⁺ channels • hypoxia • hypoxia-inducible factor 1 • hypoxic pulmonary vasoconstriction • vascular smooth muscle

Related Article:

TRPC Channel Upregulation in Chronically Hypoxic Pulmonary Arteries: The HIF-1 Bandwagon Gathers Steam

Philip I. Aaronson
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