内皮CXCR7在血管重构中的作用机制研究

Coronary heart disease is often caused by adverse vascular remodeling, including atherosclerosis and vascular restenosis. Endothelial dysfunction, resulted from mechanical and pathological insults, represents the main cellular change in the initiation of vascular remodeling. CXCR7 is a recently identified cell surface receptor, with high affinity to the chemokine CXCL12, which is genetically associated with coronary heart disease and myocardial infarction. We and colleagues recently reported that competitive binding to CXCR7 with small molecules reduced atherosclerotic lesion burden in a mouse model of atherosclerosis. Our group further demonstrated that CXCR7 is selectively expressed in the endothelium of injured arteries; inflammatory stimulation up-regulates CXCR7 in cultured endothelial cells; pharmacological inhibition of CXCR7 increases plasma CXCL12 levels and monocyte counts in the blood, without affecting plasma lipids; tissue specific deletion of endothelial CXCR7 similarly up-regulates CXCL12; patients of myocardial infarction showed increased CXCL12. Based on these observations, it is hypothesized that CXCR7 regulates vascular remodeling by direct action on endothelial repair, and by regulation of circulating CXCL12 levels, thereby inflammatory cell migration and platelet activation. This study aims to 1) clarify the role of CXCR7 in endothelial repair and vascular restenosis; 2) elucidate the role of endothelial CXCR7 in inflammatory cell trafficking and atherosclerosis; 3) explore the effect of CXCR7 on CXCL12 levels and thrombosis, both in experimental animal model and in patients of myocardial infarction. This study focuses on the mechanistic regulation of vascular remodeling by a new drug target, which centers its role in endothelium, and also possesses a systemic function in regulating levels of an important chemokine. The proposed study has potential applications in discovering new therapeutics for diseases of vascular remodeling.

冠心病的发生通常源于血管重构，而内皮功能异常是血管重构的主要诱发因素。CXCR7是新鉴定的细胞表面受体，高度亲和趋化因子CXCL12。CXCL12与冠心病和心梗在遗传上相关。申请人已报道CXCR7竞争性结合小分子抑制小鼠动脉粥样硬化，不改变血胆固醇，机制不清。近期工作表明CXCR7特异表达于损伤血管内皮，受炎症刺激诱导；抑制CXCR7升高血液单核细胞和CXCL12；敲除内皮CXCR7同样升高CXCL12；心梗患者CXCL12升高。据此本项目假设：CXCR7通过促进内皮修复、影响CXCL12水平进而影响炎症细胞迁移和血小板活化来调节血管重构性疾病。研究包括：1)澄清CXCR7在内皮修复和血管再狭窄中的作用；2)阐明其在炎症细胞迁移和动脉粥样硬化中的作用；3)探索受其调控的CXCL12水平与血栓形成的关系和临床意义。一个以内皮为核心、兼具调节系统趋化因子水平的新药靶的作用机制研究有应用价值。

冠心病的发生通常源于血管重构，而内皮功能异常是血管重构的主要诱发因素。人类疾病全基因组关联研究显示趋化因子CXCL12遗传位点与冠心病关系密切。CXCL12的CXCR7受体在冠心病中的作用机制不明。研究发现CXCR7特异表达于动脉粥样硬化斑块和动脉损伤后新生内膜的内皮细胞中，其表达受炎症因子刺激而上调。发现内皮CXCR7通过Raf-1/ERK、PI3K/AKT及Stat3信号通路，介导炎性因子（IL-1β）诱导的内皮细胞增殖，促进内皮修复，进而抑制血管再狭窄。进一步研究表明内皮CXCR7通过介导血管生成而促进缺血组织的功能恢复，对心梗后的心脏功能发挥保护作用。应用腺病毒载体在心脏内皮细胞过表达CXCR7或给予CXCR7特异性激动剂，均可以起到心脏保护作用。该研究揭示了（1）CXCR7是调节血管稳态，阻止血管再狭窄和心梗后心衰的一种新的重要机制；（2）“内皮”在血管再狭窄和心梗后心功能恢复中发挥重要作用，CXCR7是内皮发挥此作用的关键通路；（3）激动CXCR7是防治临床介入术后血管再狭窄、心衰的新策略。特别是，CXCR7促进内皮修复和血管生成的作用依赖于炎症刺激，表明CXCR7可能是病理性炎症条件下更为精准的治疗靶点，用于防治冠心病相关的血管再狭窄与心衰。拓展研究还发现，前列腺素E及其内皮受体EP4在血管再狭窄和微循环中具有重要保护作用。