Circulation Research. 2004
Published online before print July 15, 2004, doi: 10.1161/01.RES.0000138952.16382.ad
Published online before print July 15, 2004, doi: 10.1161/01.RES.0000138952.16382.ad
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Submitted on January 29, 2004
Revised on July 1, 2004
Accepted on July 2, 2004
Chronic Hypoxia-Induced Upregulation of Store-Operated and Receptor-Operated Ca2+ Channels in Pulmonary Arterial Smooth Muscle Cells
Mo-Jun Lin ;
From the Division of Pulmonary and Critical Care Medicine (M.-J.L., W.-M.Z., X.-R.Y., J.S.K.S.), Division of Gastroenterology (G.P.H.L., C.-M.T.), Johns Hopkins School of Medicine, Baltimore, Md; the Department of Physiology and Biophysics (K.-P.Y.), College of Medicine, University of South Florida, Tampa; and the Department of Physiology and Pathophysiology (M.-J.L.), Fujian Medical University, Fuzhou, Fujian, People’s Republic of China.
* To whom correspondence should be addressed. E-mail: jsks{at}welchlink.welch.jhu.edu.
Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca2+ regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca2+ entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or thapsigargin to deplete Ca2+ stores, caused dramatic increase in cation entry measured by Mn2+ quenching of fura-2 and by Ca2+ transients. OAG-induced responses were 
700-fold more resistant to La3+ inhibition than thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated thapsigargin- and OAG-induced cation entries, respectively, indicating that they were mediated through separate channels. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, inhibition of TRPC with La3+ and SK&F-96365 reversed the elevated basal [Ca2+]i in PASMCs and vascular tone in PAs of chronic hypoxic animals. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
Key words: pulmonary hypertension • transient receptor potential channels • store-operated channel • receptor-operated channel
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