肺静脉机械牵张开放牵张离子通道诱导肺动脉高压的分子机制

左心疾病相关性肺动脉高压（PH-LHD）是最常见的肺动脉高压类型，发病机制不清。在PH-LHD发生过程中，最早出现的是肺静脉压升高，即肺静脉壁机械张力升高。我们前期工作首次发现，机械牵张通过开放牵张离子通道（SAC）诱导肺静脉转化生长因子β1（TGF-β1）和干细胞因子表达升高。目前大量研究证实TGF-β1和肥大细胞均参与肺动脉高压的产生，且干细胞因子是肥大细胞主要的趋化因子,机械张力开放SAC后能激活MAPKs信号通路。由此，我们提出假设：机械张力开放SAC后通过①MAPKs信号通路导致TGF-β1表达升高②干细胞因子趋化肥大细胞聚集和脱颗粒，参与肺动脉高压的产生。本项目通过PH-LHD动物模型、离体肺静脉机械牵张模型及“平滑肌-肥大细胞”离体复合模型的研究来验证以上假设，并进一步探讨TGF-β1与肥大细胞在肺动脉高压形成中的相互关系，研究将为PH-LHD的早期治疗提供理论依据和新靶点。

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common type of pulmonary hypertension, but its pathogenesis is not clear. In the process of PH-LHD, the first occurrence is elevated pulmonary venous pressure, that is increased mechanical tension on pulmonary venous wall. Our previous work has first demonstrated that mechanical stretch induced the high expression of transforming growth factor β1 (TGF-β1) and stem cell factor (SCF) in the pulmonary vein, which was mediated by the stretch activated ion channel(SAC). At present, a large number of studies have confirmed that TGF-β1 and mast cells are involved in the production of pulmonary hypertension, and the stem cell factor is the major chemotactic factor of mast cells, mechanical stress can activate MAPKs signaling pathway through SAC. Thus, we put forward the hypothesis that mechanical tension activates SAC and then participates in the development of pulmonary hypertension through ①high expression of TGF-β1 led by MAPKs signaling pathway ②chemotactic effects of stem cell factor on the aggregation and degranulation of mast cells. This project aims to confirm the hypothesis above, and to further explore the relationship between TGF-β1 and mast cells in the formation of pulmonary hypertension through the animal model of PH-LHD, mechanical stretch of isolated pulmonary vein and "smooth muscle cells- mast cells" composite model, so as to provide a theoretical basis and a new target for early treatment of PH-LHD.