Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular Ca 2+ in pulmonary arterial smooth muscle cells

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

Research output: Contribution to journalArticle

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 concentration ([Ca]i) was elevated in PASMCs from chronically hypoxic rats because of Ca 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]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.

Original languageEnglish (US)
Pages (from-to)1528-1537
Number of pages10
JournalCirculation research
Volume98
Issue number12
DOIs
StatePublished - Jun 1 2006

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Keywords

  • Ca channels
  • Hypoxia
  • Hypoxia-inducible factor 1
  • Hypoxic pulmonary vasoconstriction
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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