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 (E-m) regulates [Ca2+](cyt) by 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+](cyt) affect 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+](cyt) was significantly higher, and resting E-m was 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-m depolarization significantly increased resting [Ca2+](cyt) and augmented agonist-mediated rises in [Ca2+](cyt) in the absence of extracellular Ca2+. These results demonstrate that reduced I-K(V), depolarized E-m, and elevated [Ca2+](cyt) may 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+](cyt) in PASMC.