Platoshyn O, Golovina V A, Bailey C L, Limsuwan A, Krick S, Juhaszova M, Seiden J E, Rubin L J, Yuan J X
Department of Medicine, University of California School of Medicine, San Diego, California 92103-8382, USA.
Am J Physiol Cell Physiol. 2000 Nov;279(5):C1540-9. doi: 10.1152/ajpcell.2000.279.5.C1540.
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+)) in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential (E(m)) regulates Ca(2+) 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+) 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+) 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+) and augmented agonist-mediated rises in Ca(2+) in the absence of extracellular Ca(2+). These results demonstrate that reduced I(K(V)), depolarized E(m), and elevated Ca(2+) 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+) in PASMC.
肺血管收缩和血管中层肥厚在很大程度上导致了肺动脉高压患者肺血管阻力的升高。肺动脉平滑肌细胞（PASMC）中胞质游离Ca2+（[Ca2+]cyt）水平升高会触发血管收缩并刺激细胞生长。膜电位（Em）通过控制Ca2+经电压依赖性Ca2+通道内流来调节[Ca2+]cyt。因此，细胞内Ca2+可能是导致肺血管收缩和血管重塑的共同信号转导元件。在PASMC中，电压门控K+（Kv）通道的活性调节静息Em。在本研究中，我们通过比较增殖期和生长停滞期PASMC的这些参数，研究了Kv电流[I(K(V))]、Em和[Ca2+]cyt的变化是否影响细胞生长。血清剥夺诱导PASMC生长停滞，而细胞外Ca2+螯合则消除PASMC生长。增殖期PASMC的静息[Ca2+]cyt显著高于生长停滞期细胞，且静息Em更去极化。同样，增殖期PASMC的全细胞I(K(V))显著减弱。此外，在没有细胞外Ca2+的情况下，Em去极化显著增加静息[Ca2+]cyt，并增强激动剂介导的[Ca2+]cyt升高。这些结果表明，I(K(V))降低、Em去极化和[Ca2+]cyt升高可能在刺激PASMC增殖中起关键作用。肺动脉高压患者的肺血管中层肥厚可能部分是由PASMC中膜去极化介导的[Ca2+]cyt增加所致。
