Hypoxia Inducible Factor 1 Mediates Hypoxia-Induced TRPC Expression and Elevated Intracellular Ca 2+ in Pulmonary Arterial Smooth Muscle Cells

Abstract

Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca 2+ concentration ([Ca 2+ ] i ) was elevated in PASMCs from chronically hypoxic rats because of Ca 2+ influx through pathways other than L-type Ca 2+ 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 Ca 2+ channels (SOCCs) and the regulation of these channels by HIF-1. Capacitative Ca 2+ entry (CCE) was enhanced in PASMCs from intrapulmonary arteries of rats exposed to CH (10% O 2 ; 21 days), and exposure to Ca 2+ -free extracellular solution or SOCC antagonists (SKF96365 or NiCl 2 ) decreased resting [Ca 2+ ] 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% O 2 ; 60 hours), and in PASMCs in which HIF-1 was overexpressed under nonhypoxic conditions. Hypoxia-induced increases in basal [Ca 2+ ] 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 Ca 2+ influx and increasing basal [Ca 2+ ] i in PASMCs and that this response is mediated by HIF-1.