血小板源性CCL2诱导内皮细胞JAM-A重排促进动脉粥样硬化的机制研究

动脉粥样硬化（AS）相关的心脑血管疾病是人类最主要的致死因素。血小板释放大量趋化因子与AS斑块形成有关，但很多机制尚不清楚。我们前期数据显示AS的血小板活性增强，可合成和释放大量趋化因子CCL2，而CCL2作用于内皮细胞引起紧密连接部位的黏附分子A（JAM-A）重排：由紧密连接部位转移至管腔侧，表现为AS斑块部位JAM-A聚集，而血小板CCL2基因敲除后JAM-A重排现象减弱。鉴于JAM-A介导单核细胞跨内皮迁移，我们认为：血小板活化释放CCL2引起JAM-A重排，诱导单核细胞跨内皮迁移，促进AS斑块形成。本项目将利用血小板特异性基因敲除小鼠和体内外实验，针对血小板源性CCL2引起JAM-A重排的调控机制、JAM-A重排如何影响单核细胞跨内皮迁移和AS斑块形成等进行研究，试图阐明CCL2-CCR2-PI3K/RHO GTPase/ZO-1调控JAM-A重排的分子机制，为AS防治提供新靶点。

Atherosclerosis (AS), an arterial chronic inflammatory disease, causes plaque formation and rupture, and AS-related cardiovascular and cerebrovascular diseases are the leading cause of death in humans. Activated platelets promote leukocytes trans-endothelial migration and chronic inflammation in AS by locally releasing chemokines. However, many mechanisms are still unknown. Our previous study showed that platelets got hyperactivity in AS and released a large amount of chemokine (C-C motif) ligand 2 (CCL2), which could induce endothelial Junctional Adhesion Molecule A (JAM-A) redistribution. In this mice model of platelet hyperactivity, JAM-A was redistributed from the inter-endothelial cell area to the apical surface and was rearrangement at the atherosclerotic plaque site. However, JAM-A redistribution was diminished in the platelet-CCL2 knockout mice. Taken together with JAM-A mediating the transendothelial migration of monocytes, we hypothesis that platelet-derived CCL2 promotes JAM-A redistribution to the luminal side and induces trans-endothelial migration of monocytes, which promotes atherosclerosis. This project is studied in vivo and in vitro of platelet special gene knockout mice models. The mechanisms of platelet-derived CCL2 inducing JAM-A redistribution and its effects on rolling, tethering, adhesion, and trans-endothelial migration of monocytes will be explored. The molecular mechanisms of CCL2-CCR2-PI3K/RHO GTPase/ZO-1 regulating JAM-A redistribution induced by platelet CCL2 will be investigated. The roles of CCL2 inducing JAM-A rearrangement in AS will be elucidated in platelet-CCL2 knockout mice, which might provide new theories and targets for AS prevention.