NFAT5通过SOCE通路调控生物力学拉伸诱导的高血压血管病变

Hypertension can lead vascular remodeling, impair the function of multiple organs, and seriously threaten human health. The biomechanical stretching induced by elevated blood pressure is an important factor in vascular remodeling. Our previous study indicated that mechanical stretch stimulation can induce vascular smooth muscle cells (VSMC) NFAT5 expression, promote the transformation, proliferation, migration and inflammatory reaction of smooth muscle cells, inhibiting NFAT5 expression was significantly decreased these effects. We also found that the mechanical tensile stimulation promotes the expression of orai-1 /SOCE pathway in VSMC and increases the opening of the calcium channel. Accordingly, we speculated that NFAT5 could regulate the vascular remodeling induced by biomechanical stretching through orai-1 /SOCE pathway. In this project, we use human VSMC and spontaneous hypertension (SHR) rats to investigate the effects of NFAT5 on the transformation, proliferation, apoptosis and fibrosis of SMC caused by biomechanical extension, analyze the changes of orai-1 /SOCE pathway and calcium influx, and to observe the effect of NFAT5/ orai-1 /SOCE on vascular remodeling in SHR rats, finally to elucidate the role and molecular mechanism of NFAT5 in promoting blood vessel remodeling, and provide new targets for the prevention and treatment of hypertensive vascular disease.

高血压可引起血管重塑，损害多器官功能，严重威胁人类健康。血压升高产生的生物力学拉伸是造成血管重塑的重要因素。我们前期研究证实，力学拉伸刺激可诱导血管平滑肌细胞（VSMC）NFAT5表达，促进平滑肌细胞转型及细胞增殖、迁移及炎症反应，抑制NFAT5表达则明显降低上述效应；同时发现力学拉伸刺激还促进VSMC中Orai-1/SOCE通路表达及钙离子通道开放增高，据此我们推测NFAT5通过Orai-1/SOCE通路调控生物力学拉伸诱导的血管重塑。本项目拟以人VSMC及自发性高血压（SHR）大鼠为研究对象，观察NFAT5对生物力学拉伸所致的SMC的转型、增殖、凋亡和纤维化的影响，分析Orai-1/SOCE通路及钙离子内流的变化情况，并观察NFAT5/Orai-1/SOCE对SHR大鼠血管重塑的影响，旨在阐明NFAT5促进高血压血管重塑的作用及分子机制，为防治高血压血管病变提供新靶点。

血压升高产生的生物力学拉伸是造成血管重塑的重要因素。本项目利用生物力学拉伸模型，体外模拟高血压产生的剪切应力。以人VSMC及自发性高血压（SHR）大鼠为研究对象，观察NFAT5/Orai-1/TRPC5对人动脉平滑肌细胞（HASMCs）及SHR大鼠血管重塑的影响。结果显示，生物力学拉伸体外实验，增加了NFAT5蛋白表达，增加了HASMCs的增殖、迁移、凋亡及炎症。此外，还增加了钙离子SOCE通路亚型Orai-1/TRPC5的蛋白表达。钙染色提示，生物力学拉伸体外实验增加了HASMCs的峰值钙摄取。转染siRNA-NFAT5后，降低了HASMCs的增殖、迁移、凋亡及炎症，减弱了SOCE通路亚型Orai-1/TRPC5的蛋白表达，减少了HASMCs的峰值钙摄取。以自发性性高血压（SHR）大鼠为研究对象，结果显示SHR大鼠血管平滑肌中NFAT5表达增加，炎症蛋白表达增加，western blotting和组织血管荧光显示，钙离子SOCE通路亚型Orai-1/TRPC5的蛋白表达增加。本课题的意义在于阐明生物力学拉伸在高血压中的作用， 阐明NFAT5促进高血压血管重塑的作用及分子机制，对制定相关有效防治措施，防治高血压血管病变提供新靶点，临床治疗提供理论基础和实用价值。