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

Chronic hypoxia (CH) causes pulmonary vasoconstriction because of increased pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation. We previously demonstrated that intracellular Ca concentration ([Ca ]i) was elevated in PASMCs from chronically hypoxic rats because of Ca 2 influx through pathways other than L-type Ca 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 channels (SOCCs) and the regulation of these channels by HIF-1. Capacitative Ca entry (CCE) was enhanced in PASMCs from intrapulmonary arteries of rats exposed to CH (10% O2; 21 days), and exposure to Ca -free extracellular solution or SOCC antagonists (SKF96365 or NiCl2) 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% O2; 60 hours), and in PASMCs in which HIF-1 was overexpressed under nonhypoxic conditions. Hypoxia-induced increases in basal [Ca ]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 influx and increasing basal [Ca ]i in PASMCs and that this response is mediated by HIF-1. (Circ Res. 2006;98:1528-1537.)