Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, United States.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, United States.
Sci Rep. 2020 May 5;10(1):7563. doi: 10.1038/s41598-020-64298-5.
Remodeling of distal pulmonary arterioles (PAs) associated with marked accumulation of pulmonary artery smooth muscle cells (PASMCs) represents one of the major pathologic features of pulmonary hypertension (PH). We have reported that the transcription factor Twist1 mediates hypoxia-induced PH. However, the mechanism by which endothelial Twist1 stimulates SMC accumulation to distal PAs in PH remains unclear. Here, we have demonstrated that Twist1 overexpression increases the expression of platelet-derived growth factor (PDGFB) in human pulmonary arterial endothelial (HPAE) cells. Hypoxia upregulates the levels of Twist1 and PDGFB in HPAE cells. When we implant hydrogel supplemented with endothelial cells (ECs) on the mouse lung, these ECs form vascular lumen structures and hypoxia upregulates PDGFB expression and stimulates accumulation of αSMA-positive cells in the gel, while knockdown of endothelial Twist1 suppresses the effects. The levels of Twist1 and PDGFB are higher in PAE cells isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy controls. IPAH patient-derived PAE cells stimulate accumulation of αSMA-positive cells in the implanted gel, while Twist1 knockdown in PAE cells inhibits the effects. Endothelial Twist1-PDGFB signaling plays a key role in αSMA-positive cell proliferation and migration in PH.
远端肺小动脉（PA）的重塑与肺动脉平滑肌细胞（PASMC）的显著积累有关，是肺动脉高压（PH）的主要病理特征之一。我们已经报道，转录因子 Twist1 介导低氧诱导的 PH。然而，内皮细胞 Twist1 刺激 PH 远端 PASMC 积累的机制尚不清楚。在这里，我们已经证明，Twist1 过表达增加了人肺动脉内皮细胞（HPAE）中血小板衍生生长因子（PDGFB）的表达。低氧上调 HPAE 细胞中 Twist1 和 PDGFB 的水平。当我们在小鼠肺上植入补充内皮细胞（EC）的水凝胶时，这些 EC 形成血管腔结构，低氧上调 PDGFB 表达并刺激凝胶中αSMA 阳性细胞的积累，而内皮细胞 Twist1 的敲低则抑制了这些作用。与健康对照组相比，特发性肺动脉高压（IPAH）患者分离的 PAE 细胞中 Twist1 和 PDGFB 的水平更高。来自 IPAH 患者的 PAE 细胞刺激植入凝胶中αSMA 阳性细胞的积累，而 PAE 细胞中 Twist1 的敲低则抑制了这种作用。内皮细胞 Twist1-PDGFB 信号通路在 PH 中 αSMA 阳性细胞的增殖和迁移中起关键作用。
