高血压变异性通过激活血管平滑肌细胞AGEs/RAGE/Rho/ROCK信号通路诱发主动脉夹层的效应与机制研究

主动脉夹层（AD）起病急，死亡率高。血管平滑肌细胞（VSMCs）表型转化是AD的重要病理改变。血压变异性（BPV）与主动脉管壁重构密切相关，但BPV在AD发生过程中的作用尚未阐明。前期研究证实AD患者BPV明显升高，提示BPV升高可能是导致AD发生的危险因素。AGEs通过调控RAGE/Rho/ROCK通路促进VSMCs表型转化。预实验提示AD患者组织AGEs含量明显升高。综上提出假设：BPV是否通过AGEs/RAGE/Rho/ROCK通路调控VSMCs表型转化进而诱发AD。本研究将扩大样本评价AD患者主动脉AGEs含量与BPV的相关性；构建动物模型以探究RAGE/Rho/ROCK通路抑制剂是否能够缓解BPV对AD发生的促进作用；构建细胞模型探索RAGE/Rho/ROCK通路抑制剂对VSMCs表型转化和增殖的影响。本研究有助于加深对AD发病机理的理解，并为靶点抑制剂用于防治AD提供实验基础。

Aortic dissection (AD) is a life-threatening condition with a high mortality rate. The phenotype switching of vascular smooth muscle cells (VSMCs) is the key pathological basis of aortic dissection. Blood pressure variability is closely correlated with vascular remodeling of the aorta, but its effect and mechanism in the occurrence of AD have not yet been elucidated. Our previous study suggested that increasing BPV could be detected in AD patients, indicating that increasing BPV may serve as a risk factor in AD. AGEs can induce phenotypic transformation of vascular smooth muscle through RAGE/Rho/ROCK pathway. We also found that AGE in tissues of AD patients was higher than that in patients with simple hypertension. Thus, we propose a hypothesis that BPV promote aortic VSMCs phenotypic alteration via activation of AGEs/RAGE/Rho/ROCK signaling pathway to induce AD. To validate this, we plan to do the followings: detect AGE level in AD patients and find the correlation between BPV and AGEs; illustrate BPV’s contribution to AD and explore the role of RAGE/Rho/ROCK in AD formation by AD animal models; explore the relationship of RAGE/Rho/ROCK pathway inhibitors and the phenotypic alteration of VSMCs by cell model. This study is meaningful for clinical understanding of AD formation and also lay a theoretical foundation for clinical medical treatment.