高血压是世界范围内的健康问题，内皮依赖的血管舒张障碍是其重要发病机制。雷帕霉素复合体1（mTORC1）的抑制剂临床应用存在高血压副作用，但mTORC1是否调控内皮依赖的血管舒张及血压尚不清楚。本项目构建内皮特异性mTORC1敲低小鼠，发现其存在内皮依赖的血管舒张障碍及高血压，代谢组学分析发现血浆PGE2显著降低。因此提出假说，mTORC1的缺失下调PGE2合成酶mPGES-1的表达，导致PGE2合成减少，进而造成血管舒张障碍及高血压。为证明该假说，将首先证实内皮mTORC1缺失通过mPGES-1/PGE2造成血管舒张障碍及高血压；机制上，将结合预实验结果证实YAP是上游介导mPGES-1调控的关键蛋白；最后将通过构建内皮mTORC1缺失YAP过表达的双基因干预动物，在体验证分子机制。本研究将揭示mTORC1/YAP/mPGES-1通路在维持内皮稳态以及血压调控中的重要作用及分子机制。

Hypertension is a worldwide health problem, and endothelium-dependent vasodilatation dysfunction is a key mechanism involved. Rapamycin shows a side effect of hypertension in clinical, but whether mTORC1 regulates endothelium-dependent vasodilatation and blood pressure is unclear. Endothelium-specific mTORC1 knockdown mice constructed by us exhibited endothelium-dependent vasodilatation dysfunction and hypertension. PGE2 content was significantly reduced in plasma of mTORC1 knockdown mice with metabolomics analysis. Therefore, we hypothesize that knockdown of mTORC1 in endothelial cells decreases mPGES-1, which is one of PGE2 synthases, leading to a reduce of PGE2, endothelium-dependent vasodilatation dysfunction and hypertension. To demonstrate that, we’ll determine whether endothelium function and blood pressure of mTORC1-knockdown mice depends on mPGES-1/PGE2. Mechanistically, we hypothesize that YAP mediates regulation of mPGES-1 and will demonstrate it with constructing specific YAP overexpression and mTORC1 knockdown mice. Our study will reveal the important role and the vital molecular mechanism of mTORC1/YAP/mPGES-1 pathway in maintaining endothelial homeostasis and normal blood pressure.