Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation

Pulmonary vasoconstriction and vascular medial hypertrophy greatly contribute to the elevated pulmonary vascular resistance in patients with pulmonary hypertension. A rise in cytosolic free Ca2+([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential ( Em) regulates [Ca2+]cytby governing Ca2+influx through voltage-dependent Ca2+channels. Thus intracellular Ca2+may serve as a shared signal transduction element that leads to pulmonary vasoconstriction and vascular remodeling. In PASMC, activity of voltage-gated K+(Kv) channels regulates resting Em. In this study, we investigated whether changes of Kv currents [ IK(V)], Em, and [Ca2+]cytaffect cell growth by comparing these parameters in proliferating and growth-arrested PASMC. Serum deprivation induced growth arrest of PASMC, whereas chelation of extracellular Ca2+abolished PASMC growth. Resting [Ca2+]cytwas significantly higher, and resting Emwas more depolarized, in proliferating PASMC than in growth-arrested cells. Consistently, whole cell IK(V)was significantly attenuated in PASMC during proliferation. Furthermore, Emdepolarization significantly increased resting [Ca2+]cytand augmented agonist-mediated rises in [Ca2+]cytin the absence of extracellular Ca2+. These results demonstrate that reduced IK(V), depolarized Em, and elevated [Ca2+]cytmay play a critical role in stimulating PASMC proliferation. Pulmonary vascular medial hypertrophy in patients with pulmonary hypertension may be partly caused by a membrane depolarization-mediated increase in [Ca2+]cytin PASMC.