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.