补体替代途径调控平滑肌细胞稳态及炎症反应促进主动脉夹层的发生机制研究

胸主动脉夹层(TAD)是死亡率最高的心血管急症之一。平滑肌细胞(SMC)稳态失衡及炎症反应是促进TAD发生的重要机制。免疫炎症系统调节血管壁稳态，包括补体系统。我们前期发现TAD患者血浆补体C3a、C5a明显升高，其受体在病变组织中表达也明显增高，且主要表达在SMC与炎症细胞中。进而在小鼠TAD模型中证实，补体系统主要通过替代途径激活，最终引起TAD，但具体机制不明。前期在青年基金资助下，我们探讨了补体C5a调节炎症反应的机制，而炎症也参与TAD发生发展。由此假设：补体替代途径调节SMC稳态促进炎症反应，同时补体系统激活也可直接引起过度的炎症反应，促进TAD发生发展。本研究拟在补体相关基因(C4、FB、C3aR、C5aR)敲除小鼠中诱导TAD模型，结合骨髓移植、病理、细胞及分子生物学技术，明确补体替代途径如何影响SMC稳态(表型转化、存活、增殖等)及炎症反应，促进TAD发生发展的具体机制。

Thoracic aortic dissection (TAD) is one of cardiovascular emergencies which have high mortality. Recent studies have found that imbalance of smooth muscle cell(SMC) homeostasis（phenotype change, survival, proliferation) and inflammatory response contribute to TAD formation. The immune and inflammatory system regulate vascular wall homeostasis, including the complement system. Our previous study found that the level of plasma complement 3a and complement 5a increased significantly in aortic dissection patients, the expression of its receptors also increased significantly in aorta tissue of aortic dissection patients, and also its receptor mainly expressed in smooth muscle cell and inflammatory cell. Furthermore, we proved that alternative pathway of complement cascade promote aortic dissection formation. However the detailed role of complement in aortic dissection formation remains unclear. Previous study supported by NSFC Youth Program, we showed the mechanism of complement 5a on inflammatory response, and inflammation also involved in the TAD formation. Therefore, we hypothesized that complement system may regulate SMC homeostasis and inflammatory response and promote the development of TAD. In the present study, we will induce aortic dissection formation in wild type and complement related gene(C4, Factor B, C3aR and c5aR) knockout mice, combined with bone marrow transplantation, ultrasonography, pathology, cellular and molecular biology technique, to clarify the role of complement system in aortic dissection formation. Our results indicate a new and potentially promising therapeutic application of complement system related inhibitor to the treatment of aortic dissection.