肺动脉高压（PAH）的主要病因是肺血管重构导致肺动脉腔隙狭窄。肺动脉内皮细胞、平滑肌细胞以及成纤维细胞在肺动脉重构中均有重要作用。内皮间质转化（EndMT）在心血管发育（包括肺动脉发育）、各种血管疾病（如动脉粥样硬化和血管再狭窄时内膜增生）以及伤口愈合中发挥重要作用。EndMT是否参与PAH时肺血管重构尚未阐明。我们的预实验发现，低氧诱导PAH大鼠肺动脉中EndMT标记蛋白（波形蛋白）表达显著增加，并主要表达在肺动脉的内膜和外膜，提示EndMT可能导致PAH时肺血管重构。本项目拟通过在体动物与细胞实验，阐明EndMT在PAH肺血管重构发生过程中的重要作用，在此基础上，在体动物与细胞实验相结合，生物信息学与分子生物学技术相结合，从三个方面（miRNAs网络、转录和翻译水平）综合探讨导致PAH时EndMT的分子网络机制。本项目将有助于阐明PAH的发病机制，为寻找防治PAH的新靶点奠定基础。

The predominant cause of pulmonary arterial hypertension(PAH) is loss of vascular luminal cross section due to vascular remodeling. Pulmonary arterial endothelial cells, smooth muscle cells and fibroblasts play important roles in pulmonary vascular remodeling. Endothelial-mesenchymal transition (EndMT) plays critical roles in cardiovascular development (including pulmonary artery), various vascular diseases (such as neointima thickening observed in atherosclerosis and restenosis) and wound healing. However, the role of EndMT in vascular remodeling in PAH remains unclear. Our pilot study showed that the expression of vimentin, the EndMT marker protein, was up-regulated in pulmonary arteries in hypoxia-induced PAH rats, especially in intima and adventitia, suggesting that EndMT may contribute to pulmonary vascular remodeling in PAH. We will be planning to explore the important/potential role of EndMT in mediating the pulmonary vascular remodeling in PAH rats. Furthermore, we will investigate the underlying molecular network mechanisms (miRNAs network, transcriptional level and translational level) responsible for the role of EndMT in PAH. This study will contribute to the understanding of the pathogenesis of PAH, and provide new therapies to seek for new targets for new drug research and development.

肺动脉高压（PAH）的主要病因是肺血管重构导致肺动脉腔隙狭窄。肺动脉内皮细胞、平滑肌细胞以及成纤维细胞在肺动脉重构中均有重要作用。内皮间质转化（EndMT）在心血管发育（包括肺动脉发育）、各种血管疾病（如动脉粥样硬化和血管再狭窄时内膜增生）以及伤口愈合中发挥重要作用。EndMT是否参与PAH时肺血管重构尚未阐明。本项目拟通过在体动物与细胞实验，阐明EndMT在PAH肺血管重构发生过程中的重要作用，在此基础上，在体动物与细胞实验相结合，生物信息学与分子生物学技术相结合，从三个方面（miRNAs网络、转录和翻译水平）综合探讨导致PAH时EndMT的分子网络机制。结果发现：（1）利用生物学信息技术从大量miRNAs中筛选得到的22 个miRNAs 同时参与TGF-beta/BMP、低氧和炎症信号通路，可能与PAH 时EndMT 相关。（2）miR-27a通过靶向调控Smad5抑制Smad5/Id2/Twist/Snail信号通路介导低氧性肺动脉高压内皮细胞间质转化。（3）4-PBA通过降低eIF2α磷酸化水平，抑制内质网应激，进而抑制肺动脉内皮细胞发生间质转化缓解低氧肺动脉高压肺血管重构。（4）EGCG通过调节KLF-4/MFN-2/p-Erk信号通路抑制低氧诱导肺动脉高压时肺动脉内皮细胞线粒体分裂及内皮间质转化。本项目主要研究了EndMT在PAH肺血管重构发生过程中的重要作用及分子机制，将有助于阐明PAH的发病机制，为寻找防治PAH的新靶点奠定基础。