Xu Jingjing, Li Xiangnan, Zhou Siqi, Wang Rui, Wu Mengxi, Tan Cheng, Chen Jingyu, Wang Zhiping
Department of Anesthesiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi, Jiangsu Province, China.
Department of Anesthesiology, The Third People's Hospital of Yancheng Yancheng, Jiangsu Province, China.
Am J Transl Res. 2021 Mar 15;13(3):1458-1470. eCollection 2021.
Pulmonary vascular remodeling due to aberrant proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) is the main characteristic of pulmonary arterial hypertension (PAH). CXCR4 is a specific stem cell surface receptor of cytokine CXCL12 which could regulate homing of hematopoietic progenitor cells and their mobilization. There is evidence that bone marrow-derived CXCR4 proangiogenic cell accumulation take an important part in the development of pulmonary arterial hypertension; however, the underlying mechanisms still remain unknown. Here, we explored the expression profile of CXCR4 both in hypoxia rats and PAH patients by measuring proliferation and migration of PASMCs. We performed western blot analysis to detect downstream molecules. We demonstrated that CXCR4 expression level was increased in both rats exposed to chronic hypoxia and PAH patients in reconstructed pulmonary arterioles. The inhibition of CXCR4 expression slowed down the process of hypoxic-PAH by reducing the mean right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in vivo experimental mode. CXCR4 overexpression and inhibition regulated the cell growth of PASMCs in hypoxia condition, which are the critical cellular events in vascular disease. Furthermore, activation of β-catenin signaling and upregulation of CXCR4 could be blocked by AMD3100 both in vivo and vitro. Taken together, inhibition of CXCR4 expression could downregulate β-catenin, reduced pulmonary artery smooth muscle cell proliferation, and ameliorated pulmonary vascular remodeling in hypoxia rats. These findings suggest that CXCL12/CXCR4 is critical in driving PAH and uncover a correlation between β-catenin dependent signaling.
由于肺动脉平滑肌细胞（PASMCs）异常增殖和迁移导致的肺血管重塑是肺动脉高压（PAH）的主要特征。CXCR4是细胞因子CXCL12的特异性干细胞表面受体，可调节造血祖细胞的归巢及其动员。有证据表明，骨髓来源的CXCR4促血管生成细胞积累在肺动脉高压的发展中起重要作用；然而，其潜在机制仍不清楚。在此，我们通过测量PASMCs的增殖和迁移，探讨了CXCR4在缺氧大鼠和PAH患者中的表达谱。我们进行了蛋白质印迹分析以检测下游分子。我们证明，在暴露于慢性缺氧的大鼠和PAH患者的重建肺小动脉中，CXCR4表达水平均升高。在体内实验模式中，抑制CXCR4表达可通过降低平均右心室收缩压、右心室肥大和肺血管重塑来减缓缺氧性PAH的进程。CXCR4的过表达和抑制在缺氧条件下调节PASMCs的细胞生长，这是血管疾病中的关键细胞事件。此外，AMD3100在体内和体外均可阻断β-连环蛋白信号的激活和CXCR4的上调。综上所述，抑制CXCR4表达可下调β-连环蛋白，减少肺动脉平滑肌细胞增殖，并改善缺氧大鼠的肺血管重塑。这些发现表明，CXCL12/CXCR4在驱动PAH中起关键作用，并揭示了β-连环蛋白依赖性信号之间的相关性。
