S1PR2上调导致滋养血管功能障碍在主动脉夹层发病中的作用机制研究

主动脉夹层（AD）是一种致死率极高的疾病，主动脉管壁水肿和滋养血管内膜屏障破坏为其重要病理表现。我们前期实验发现AD组织中鞘磷脂代谢产物受体S1PR2表达上调，该受体可抑制血管内皮细胞（VEC）表达连接蛋白并抑制NO释放，同时促进外周阻力血管平滑肌细胞（VSMC）收缩。据此我们推测S1PR2上调可能通过导致滋养血管内膜屏障破坏，同时收缩外周阻力血管增加滋养血管灌注压，使液体渗入主动脉间质增加，引起管壁水肿，诱发AD。我们拟进行体外实验验证AD组织来源的原代VEC、VSMC中S1PR2上调后可发生上诉变化并研究其下游通路机制；通过建立血管组织特异性过表达S1PR2小鼠模型，观察是否会出现滋养血管功能障碍、主动脉管壁水肿并且诱发AD，验证S1PR2通路抑制剂能否预防AD发生。从而阐明S1PR2上调、滋养血管功能障碍与AD形成之间的联系，为探索AD的发病机制、寻找早期诊断和预防方法提供理论依据。

Aortic dissection (AD) is a lethal disease with high morbidity and mortality. Interstitial edema of aortic wall and impaired intima of vasa vasorum are the key histopathological changes for AD. Our previous work demonstrated that expression of sphingosine-1-phosphate receptor type 2 (S1PR2) was significantly increased in AD compared with healthy control. The activation of S1PR2 led to the suppression of proteins responsible for vascular endothelial (VEC) connection, release of nitric oxide (NO), and promote the contraction of vascular smooth muscle cells (VSMC), which contributed to elevated microvascular pressure. Therefore, we hypothesize that the overexpression of S1PR2 in AD may impair the vascular intima and elevate the pressure within the vasa vasorum, which then force the fluid to seep into the aortic medium and result in aortic wall edema. In this study, we will verify these pathological changes using VEC and VSMC isolated from aorta of patients with AD. Furthermore, we will over-express S1PR2 specifically in VEC and VSMC using lentivirus, and examine the integrity of vascular intima, release of NO and the contractility of VSMC. To further test our hypothesis in vivo, we will overexpress S1PR2 in the aorta of mouse model, and examine the incidence of AD. This work will help us better understand the etiology of AD, which may lead to improved diagnosis, prevention, and treatment for this condition.