磷酸酶SHP2介导的内化机制在绝经后血管屏障稳态失衡中的作用研究

女性心血管疾病发生风险在绝经后明显上升，雌激素下降引起的血管衰老在其中发挥重要作用。血管屏障稳态失衡是血管衰老的典型病理特征，然而机制研究缺乏。我们前期研究发现小鼠去势后血管内皮屏障受损，雌激素对内皮屏障具有保护作用；机制上，雌激素活化磷酸酶SHP2，而SHP2缺失破坏内皮屏障完整性，并导致屏障关键膜蛋白VE-Cad内化。我们提出科学假说：绝经后血管内皮屏障稳态失衡是失去雌激素的保护作用导致的，雌激素通过SHP2介导的内化机制保护内皮屏障完整性。我们拟开展动物、细胞、临床样品三层次研究：在转基因小鼠中利用去势、内皮屏障损伤模型，明确SHP2在雌激素调控血管屏障完整性中的关键作用；内皮细胞中解析雌激素调控SHP2活化及内化作用的分子机制；分析临床血管组织研究绝经前后血管屏障结构改变及干预措施。课题将为诠释中老年女性血管机能退化提供新视角，为绝经激素治疗和新的干预策略提供理论基础与实验依据。

The vascular aging caused by estrogen deficiency plays an important role in the increased risk of CVD after menopause. The vascular endothelial barrier disruption is a typical pathological feature of vascular aging, whereas its mechanism is largely unknown. Our preliminary data showed mouse Ovariectomy caused vascular endothelial barrier dysfunction. In vitro, we showed estrogen activated phosphatase SHP2, whose knockdown markedly disrupted endothelial barrier and increased the internalization of VE-Cadherin, the key membrane protein in maintaining vascular barrier. Thus we hypothesis that vascular endothelial barrier disruption after menopause is resulted by estrogen deficiency; estrogen protects endothelial barrier integrity via internalization mechanism mediated by SHP2. We are going to test our hypotheses by conducting research in mouse models, endothelial cells and clinical samples. By combining Ovariectomy and the transgenic mouse model with constituted activated SHP2 in endothelium, we further explore the role of estrogen, mediated by SHP2, in the integrity vascular barrier in vivo. In addition, the molecular mechanisms of SHP2 in regulating estrogen signaling and VE-Cadherin internalization will be investigated. Finally the changes of vascular barrier before and after menopause will be evaluated in ex vivo tissues as well as the interventions in improving the vascular integrity. Our studies will bring novel insights for vascular degeneration in elderly women as well as scientific basis for menopause hormone therapy and potential intervention.