Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, which exists in both pulmonary arteries and pulmonary veins. Pulmonary vascular remodeling stems from excessive proliferation of pulmonary vascular myocytes. Platelet-derived growth factor-BB (PDGF-BB) is a vital vascular regulator whose level increases in PH human lungs. Although the mechanisms by which pulmonary arterial smooth muscle cells respond to PDGF-BB have been studied extensively, the effects of PDGF-BB on pulmonary venous smooth muscle cells (PVSMCs) remain unknown. We herein examined the involvement of calcium sensing receptor (CaSR) in PDGF-BB-induced PVSMCs proliferation under hypoxic conditions. In PVSMCs isolated from rat intrapulmonary veins, PDGF-BB increased the cell number and DNA synthesis under normoxic and hypoxic conditions, which was accompanied by upregulated CaSR expression. The influences of PDGF-BB on proliferation and CaSR expression in hypoxic PVSMCs were greater than that in normoxic PVSMCs. In hypoxic PVSMCs superfused with Ca²⁺-free solution, restoration of extracellular Ca²⁺ induced an increase of [Ca²⁺]_i, which was significantly smaller than that in PDGF-BB-treated hypoxic PVSMCs. The positive CaSR modulator spermine enhanced, whereas the negative CaSR modulator NPS2143 attenuated, the extracellular Ca²⁺-induced [Ca²⁺]_i increase in PDGF-BB-treated hypoxic PVSMCs. Furthermore, the spermine enhanced, whereas the NPS2143 inhibited, PDGF-BB-induced proliferation in hypoxic PVSMCs. Silencing CaSR with siRNA attenuated the extracellular Ca²⁺-induced [Ca²⁺]_i increase in PDGF-BB-treated hypoxic PVSMCs and inhibited PDGF-BB-induced proliferation in hypoxic PVSMCs. In conclusion, these results demonstrated that CaSR mediating PDGF-BB-induced excessive PVSMCs proliferation is an important mechanism involved in the initiation and progression of PVSMCs proliferation under hypoxic conditions.

肺动脉高压（PH）的特点是肺血管重塑，存在于肺动脉和肺静脉中。肺血管重塑源于肺血管肌细胞的过度增殖。血小板衍生生长因子-BB (PDGF-BB) 是一种重要的血管调节剂，其水平在 PH 人肺中增加。尽管肺动脉平滑肌细胞对 PDGF-BB 的反应机制已被广泛研究，但 PDGF-BB 对肺静脉平滑肌细胞 (PVSMCs) 的影响仍然未知。我们在此检查了钙传感受体 (CaSR) 在缺氧条件下参与 PDGF-BB 诱导的 PVSMCs 增殖。在从大鼠肺静脉分离的 PVSMC 中，PDGF-BB 在常氧和低氧条件下增加了细胞数量和 DNA 合成，伴随着上调的 CaSR 表达。PDGF-BB对缺氧PVSMCs增殖和CaSR表达的影响大于常氧PVSMCs。在用 Ca 灌注的缺氧 PVSMC 中²⁺游离溶液，细胞外Ca ²⁺的恢复诱导[Ca ²⁺ ] _i增加，明显小于PDGF-BB处理的缺氧PVSMCs。正CaSR调节剂精胺增强，而负CaSR调节剂NPS2143减弱，PDGF-BB处理的缺氧PVSMC中细胞外Ca ²⁺诱导的[Ca ²⁺ ] _i增加。此外，精胺增强，而 NPS2143 抑制 PDGF-BB 诱导的缺氧 PVSMC 增殖。用 siRNA 沉默 CaSR 减弱了细胞外 Ca ²⁺诱导的 [Ca ²⁺ ] _iPDGF-BB 处理的缺氧 PVSMCs 增加并抑制 PDGF-BB 诱导的缺氧 PVSMCs 增殖。总之，这些结果表明，CaSR介导PDGF-BB诱导的PVSMCs过度增殖是缺氧条件下PVSMCs增殖起始和进展的重要机制。