title: 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 Ca(2+) ([Ca(2+)](cyt)) in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential (E(m)) regulates [Ca(2+)](cyt) by governing Ca(2+) influx through voltage-dependent Ca(2+) channels. Thus intracellular Ca(2+) 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 [Ca(2+)](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 Ca(2+) abolished PASMC growth. Resting [Ca(2+)](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 [Ca(2+)](cyt) and augmented agonist-mediated rises in [Ca(2+)](cyt) in the absence of extracellular Ca(2+). These results demonstrate that reduced I(K(V)), depolarized E(m), and elevated [Ca(2+)](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 [Ca(2+)](cyt) in PASMC.
authors.affiliation: Department of Medicine, University of California School of Medicine, San Diego, California 92103-8382, USA.
authors.forename: O
authors.initials: O
authors.lastname: Platoshyn
authors.forename: V A
authors.initials: VA
authors.lastname: Golovina
authors.forename: C L
authors.initials: CL
authors.lastname: Bailey
authors.forename: A
authors.initials: A
authors.lastname: Limsuwan
authors.forename: S
authors.initials: S
authors.lastname: Krick
authors.forename: M
authors.initials: M
authors.lastname: Juhaszova
authors.forename: J E
authors.initials: JE
authors.lastname: Seiden
authors.forename: L J
authors.initials: LJ
authors.lastname: Rubin
authors.forename: J X
authors.initials: JX
authors.lastname: Yuan
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001790:Blood Physiological Phenomena; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005110:Extracellular Space / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000502:physiology; D011651:Pulmonary Artery / Q000166:cytology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002614:Chelating Agents; D003470:Culture Media; D007476:Ionophores; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D011188:Potassium; D002118:Calcium