hUC-MSCs源性外泌体miRNA-145-5p介导的SAC/PI3K/AKT2通路调控肺动脉高压大鼠肺静脉平滑肌细胞表型转化的机制研究

左心疾病引起肺动脉高压（PH-LHD）机制不清。我们发现：疾病早期肺静脉平滑肌细胞（PVSMC）在机械张力激活牵张离子通道（SAC）后分泌基质金属蛋白酶9（MMP-9），参与肺血管重构（国自然：81770368）。已知VSMC只有从正常收缩表型转化为合成表型才能分泌MMP-9，且AKT2调节VSMC表型转化；脐带间充质干细胞（hUC-MSCs）对PH-LHD治疗有效，但机制不详。预实验发现PH-LHD大鼠行hUC-MSCs干预后肺静脉miRNA-145-5p表达下降，AKT2表达升高，肺动脉高压缓解，又因外泌体（EXO）是MSCs发挥作用的主要介质，故推测：1.机械牵张肺静脉诱导SAC/PI3K/AKT2调控PVSMC表型转化；2.hUC-MSCs源性EXO下调miRNA-145-5p，抑制PVSMC表型转化和肺血管重构。本研究拟证实推测，为PH-LHD发病机制研究及早期治疗提供新思路。

The pathogenesis of pulmonary hypertension due to left heart disease (PH-LHD) remains unknown. Supported by the National Natural Science Foundation (NO. 81770368), our previous work has demonstrated that secretion of matrix metalloproteinase 9 (MMP-9) in the pulmonary vein smooth muscle cells (PVSMC) in early stage of disease, which is induced by mechanical stretch via activating the stretch activated ion channels (SAC), is involved in pulmonary vascular remodeling. It is known that the VSMC secretes MMP-9 only when it is converted from normal contractile phenotype to synthetic phenotype, and the phenotypic transformation of VSMC is modulated by AKT2. Umbilical cord blood mesenchymal stem cells (hUC-MSCs) are effective to treat PH-LHD, but the underlying mechanism is not clear. Our preliminary experiments showed that in PH-LHD rats, after intervention with hUC-MSCs, the expression of miRNA-145-5p was down-regulated while the expression of AKT2 was up-regulated in pulmonary veins, and the pulmonary hypertension was relieved. Since exosomes (EXO) are the primary mediators for MSCs to function, we hypothesize that: 1. Mechanical stretch of pulmonary vein induces SAC/PI3K/AKT2 pathway to regulate the phenotypic transformation of PVSMC; 2. hUC-MSCs-derived EXO down-regulates miRNA-145-5p and inhibits the phenotypic transformation of PVSMC as well as pulmonary vascular remodeling. Our project aims to investigate novel pathogenesis and early treatment strategy of PH-LHD.