Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation

Abstract

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 ( E_m) 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 E_m. In this study, we investigated whether changes of Kv currents [ I_K(V)], E_m, 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 E_mwas more depolarized, in proliferating PASMC than in growth-arrested cells. Consistently, whole cell I_K(V)was significantly attenuated in PASMC during proliferation. Furthermore, E_mdepolarization significantly increased resting [Ca²⁺]_cytand augmented agonist-mediated rises in [Ca²⁺]_cytin the absence of extracellular Ca²⁺. These results demonstrate that reduced I_K(V), depolarized E_m, 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.