Pulmonary arterial hypertension (PAH) is a rare and lethal disease characterized by vascular remodeling and vasoconstriction, which is associated with increased intracellular calcium ion (Ca2+) concentration. Platelet-derived growth factor-BB (PDGF-BB) is the most potent mitogen for pulmonary arterial smooth muscle cells (PASMCs) and involved in vascular remodeling during PAH development. PDGF signaling has been proved to participate in maintaining Ca2+ homeostasis of PASMCs, however, the mechanism needs to be further elucidated. Here we illuminate that the expression of PMCA4 was downregulated in PASMCs after PDGF-BB stimulation, which was abolished by MEK/ERK inhibition. Functionally, suppression of PMCA4 attenuated the intracellular Ca2+ ([Ca2+]i) clearance in PASMCs after Ca2+ entry, promoting cell proliferation and elevating cells locomotion through mediating formation of focal adhesion. Additionally, the expression of PMCA4 was decreased in the pulmonary artery of MCT- or hypoxia-induced PAH rats. Moreover, knockdown of PMCA4 could increase the right ventricular systolic pressure and wall thickness of pulmonary artery in rats raised under normal condition. Taken together, our data proved the importance of the PDGF/MEK/ERK/PMCA4 axis in intracellular Ca2+ homeostasis in PASMCs, indicating a functional role of PMCA4 in pulmonary arterial remodeling and PAH development.

中文翻译：

---

PDGF / MEK / ERK轴通过减少肺动脉平滑肌细胞中血浆膜Ca2 +泵PMCA4的丰度来抑制Ca2 +清除。

肺动脉高压（PAH）是一种罕见的致死性疾病，其特征在于血管重塑和血管收缩，这与细胞内钙离子（Ca2 +）浓度升高有关。血小板衍生生长因子-BB（PDGF-BB）是肺动脉平滑肌细胞（PASMC）最有效的促分裂原，在PAH发育过程中参与血管重塑。已经证明PDGF信号传导参与维持PASMC的Ca 2+稳态，但是，该机制需要进一步阐明。在这里，我们阐明了PDGF-BB刺激后，PASMCs中PMCA4的表达下调，而MEK / ERK抑制作用取消了PMCA4的表达。从功能上讲，PMCA4的抑制作用减弱了进入Ca2 +后PASMC中细胞内Ca2 +（[Ca2 +] i）的清除率，通过介导粘着斑形成促进细胞增殖并提高细胞运动。另外，在MCT或缺氧诱导的PAH大鼠的肺动脉中，PMCA4的表达降低。此外，敲低PMCA4可以增加正常条件下饲养的大鼠的右心室收缩压和肺动脉壁厚度。综上所述，我们的数据证明了PDGF / MEK / ERK / PMCA4轴在PASMCs细胞内Ca2 +稳态中的重要性，表明PMCA4在肺动脉重构和PAH发育中的功能性作用。敲低PMCA4可以增加正常状态下大鼠的右心室收缩压和肺动脉壁厚度。综上所述，我们的数据证明了PDGF / MEK / ERK / PMCA4轴在PASMCs细胞内Ca2 +稳态中的重要性，表明PMCA4在肺动脉重构和PAH发育中的功能性作用。敲低PMCA4可以增加正常状态下大鼠的右心室收缩压和肺动脉壁厚度。综上所述，我们的数据证明了PDGF / MEK / ERK / PMCA4轴在PASMCs细胞内Ca2 +稳态中的重要性，表明PMCA4在肺动脉重构和PAH发育中的功能性作用。