Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation |
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Authors: | Platoshyn O Golovina V A Bailey C L Limsuwan A Krick S Juhaszova M Seiden J E Rubin L J Yuan J X |
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Institution: | Department of Medicine, University of California School of Medicine, San Diego, California 92103-8382, USA. |
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Abstract: | Pulmonary vasoconstriction and vascularmedial hypertrophy greatly contribute to the elevated pulmonaryvascular resistance in patients with pulmonary hypertension. A rise incytosolic free Ca2+ (Ca2+]cyt)in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential (Em) regulatesCa2+]cyt by governing Ca2+influx through voltage-dependent Ca2+ channels. Thusintracellular Ca2+ may serve as a shared signaltransduction element that leads to pulmonary vasoconstriction andvascular remodeling. In PASMC, activity of voltage-gated K+(Kv) channels regulates resting Em. In thisstudy, we investigated whether changes of Kv currentsIK(V)], Em, andCa2+]cyt affect cell growth by comparingthese parameters in proliferating and growth-arrested PASMC. Serumdeprivation induced growth arrest of PASMC, whereas chelation ofextracellular Ca2+ abolished PASMC growth. RestingCa2+]cyt was significantly higher, andresting Em was more depolarized, inproliferating PASMC than in growth-arrested cells. Consistently, wholecell IK(V) was significantly attenuated in PASMCduring proliferation. Furthermore, Emdepolarization significantly increased restingCa2+]cyt and augmented agonist-mediatedrises in Ca2+]cyt in the absence ofextracellular Ca2+. These results demonstrate that reducedIK(V), depolarized Em, and elevated Ca2+]cyt may play a criticalrole in stimulating PASMC proliferation. Pulmonary vascular medialhypertrophy in patients with pulmonary hypertension may be partlycaused by a membrane depolarization-mediated increase inCa2+]cyt in PASMC. |
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