The Na+/H+ exchanger contributes to increased smooth muscle proliferation and migration in a rat model of pulmonary arterial hypertension.
The Na+/H+ exchanger contributes to increased smooth muscle proliferation and migration in a rat model of pulmonary arterial hypertension.
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DOI：
10.14814/phy2.12729
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发表时间：
2016-03
影响因子：
2.5
通讯作者：
Shimoda LA
中科院分区：
文献类型：
--
作者：
Huetsch JC;Jiang H;Larrain C;Shimoda LA
小肺血管的肌力增加，涉及肺动脉平滑肌细胞（PASMC）增殖和迁移的增强，是肺动脉高压（PH）发展的血管重塑的关键组成部分。生长因子和缺氧等刺激通过上调 Na+/H+ 交换器 (NHE) 诱导 PASMC 碱化、增殖和迁移，抑制 NHE 可以防止缺氧诱导的血管重塑和 PH 的发生。我们想要探讨 NHE 是否也是肺动脉高压 (PAH) 模型中病理性 PASMC 增殖和迁移所必需的，PAH 是一种与持续缺氧无关的严重肺动脉高压。 PASMCs 是从暴露于 SU5416 缺氧 (SuHx) 后恢复常氧的大鼠和媒介物对照中分离出来的。我们使用 pH 敏感荧光染料 BCECF-AM 测量了静息细胞内 pH (pH i) 和 NHE 活性。分别使用 BrdU 掺入和 Transwell 过滤器评估 PASMC 增殖和迁移。 SuHx PASMC 中的 NHE 活性增加，但静息 pH i 没有变化。相对于对照组，SuHx PASMC 还表现出增殖和迁移增加，在 NHE 药物抑制的情况下，增殖和迁移减弱。我们的研究结果表明，NHE 活性的增加有助于 PAH SuHx 模型中的病理性 PASMC 功能，尽管这种效应似乎不是由 pH i 稳态的整体变化介导的。
Increased muscularity of small pulmonary vessels, involving enhanced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a key component of the vascular remodeling underlying the development of pulmonary hypertension (PH). Stimuli such as growth factors and hypoxia induce PASMC alkalinization, proliferation, and migration through upregulation of the Na+/H+ exchanger (NHE), inhibition of which prevents the development of hypoxia‐induced vascular remodeling and PH. We wanted to explore whether NHE was also necessary for pathologic PASMC proliferation and migration in a model of pulmonary arterial hypertension (PAH), a severe form of PH not associated with persistent hypoxia. PASMCs were isolated from rats exposed to SU5416‐hypoxia (SuHx) followed by return to normoxia and from vehicle controls. We measured resting intracellular pH (pH i) and NHE activity using the pH‐sensitive fluorescent dye BCECF‐AM. PASMC proliferation and migration were assessed using BrdU incorporation and transwell filters, respectively. NHE activity was increased in SuHx PASMCs, although resting pH i was unchanged. SuHx PASMCs also exhibited increased proliferation and migration relative to controls, which was attenuated in the setting of pharmacologic inhibition of NHE. Our findings suggest that increased NHE activity contributes to pathologic PASMC function in the SuHx model of PAH, although this effect does not appear to be mediated by global changes in pH i homeostasis.