补体调节的血管外周免疫微环境在血管损伤中的机制研究

血管损伤是一种慢性低度的免疫炎症反应过程，认识免疫炎症细胞与血管微环境的关系对阐明血管损伤规律及其细胞分子机制至关重要。近期研究发现血管外膜成纤维细胞、脂肪细胞，单核巨噬细胞及其细胞外基质等形成的免疫微环境乃为血管损伤的始发环节。我们前期研究发现血管损伤时大量巨噬细胞在血管外周组织浸润，并伴有补体C3表达增加；利用C3基因敲除小鼠制备高血压模型可使外周巨噬细胞浸润减少，血管损伤程度减轻。因此我们假设外膜巨噬细胞激活介导的补体反应在血管损伤中起重要作用。本项目以免疫-炎症反应调节血管微环境为切入点，研究：1）血管损伤诱导的外膜组织巨噬细胞浸润及补体激活效应；2）补体介导的炎症因子释放调控高血压血管损伤机制；3）整体模型干预巨噬细胞及补体途径激活，观察外膜炎症反应的调节作用；4）利用骨髓重建技术条件性抑制巨噬细胞补体途径激活，阐释巨噬细胞介导的血管炎症反应机制，为防治早期血管损伤提供新思路。

Chronic low-grade immune and inflammatory processes are increasingly recognized as major pathogenic components of vascular injury. Once the integrity of vessel wall is compromised, the ability of vascular microenvironment to control the celluar and extracellular events, in particular those which associated with immunity and inflammation, becomes depressed. More over, current studies demonstrated that breaking the balance of perivascular immune microenvironment, which includes immune cells, adipocytes, adventitial fibroblasts and extracellular matrix, induces the expression of inflammatory factors in perivascular tissue, is involved in developing vascular injury. In these processes, Macrophages, T and B lymphocytes, and dendritic cell are present in the perivascular tissue of injury. Similarly, increased expression of inflammatory factors, cytokines, vasoactive substance and extracellular matrix in the processes of vascular remodeling are thought to contribute directly to further recruitment of inflammatory cells and activation of vascular cells and pericytes, which finally contributes to the pathological processes of vascular injury. Therefore clarifying the relationship between immune/inflammation and perivascular microenvironment will help us to better understand the mechanisms of vascular injury. Recently,our research suggest that hypertensive vascular injury induce macrophage infiltration around perivasular tissue and the expression of complement C3 in perivascular tissue especially in macrophages significantly increased. Interestingly, we further found macrophage infiltration and vascular remodeling were attenuated in hypertensive C3-/- mice compared with C3+/+ mice. Based on these results,we hypothesized that perivascular macrophage infiltration induced complement activation, activated complement peptide (C3a and C5a) induced the expression of inflammatory factors and broke the homeostasis of perivascular microenvironment, and finally contributed to the processes of hypertensive vascular injury.This project based on the regulation of perivascular microenvironment mediated by immunity and inflammation,in particular the effects of complement activation in macrophage to hypertensive vacular injury.，and study: 1.The processes of vascualr injury induced perivascular macrophage infiltration and complement activation; 2.The mechanism of hypertensive vascular injury mediated by complement induced inflammatory factors; 3. The pathological changes of perivascular inflammation after inhibiting macrophage activation and complement peptide in vivo; 4. To explain the vascular inflammation induced by macrophage by using bone marrow transplantation methods. Finally, we want to provide new strategies for preventing and therapying hypertensive vascular injury.