内皮源性外泌体靶向动员EPC加速损伤后再内皮化进程及机制研究

Retarded re-endothelialization after stent implantation is closely related to the in-stent restenosis, however, the reduced mobilization and dysfunction of endothelial progenitor cell (EPC) contribute greatly to delayed re-endothelialization. It is believed that SDF-1 and its receptor CXCR4 play a key role of EPC mobilization, and the SDF-1/CXCR4 axis is regulated by many miRNAs, however, the mechanism of SDF-1/CXCR4 axis regulation and bone marrow EPC targeted mobilization is not clear. Based on our investigative study and foreign literature review, we propose a novel concept that endothelial cell (EC) derived exosome is a miRNA transporter for bone marrow EPC targeted mobilization and SDF-1/CXCR4 axis activation. Therefore, our present study intends to elucidate the role and mechanism of EC derived exosomes on bone marrow EPC targeted mobilization in vivo and in vitro. Finding of this scheduled study may be expected to give a new idea of prevention in restenosis .

支架植入术后再内皮化延迟与支架内再狭窄的发生密切相关，而内皮祖细胞（EPC）动员减少及功能减低是再内皮化延迟的重要原因。目前认为SDF-1及其受体CXCR4在EPC的动员过程中起了关键作用，且SDF-1/CXCR4轴受多种miRNA调控，但这些miRNA通过何种途径调控SDF-1/CXCR4轴并靶向动员骨髓EPC的机制尚不清楚。我们根据文献及探索性研究推测，内皮细胞（EC）源性外泌体是体内靶向传递miRNA至骨髓活化SDF-1/CXCR4轴，动员EPC的转运载体。故本研究拟在细胞和动物水平阐明EC源性外泌体靶向动员骨髓EPC的作用及机制，结果将有望为再狭窄的防治提供新思路。

外泌体是体内精密而有序的物流系统，在细胞间通讯中具有明显的靶向性，且由于其富含多种血管活性物质，可能是防治冠心病的潜在途径。在本项目的资助下，我们探讨了外泌体在冠心病防治中的作用，重点研究了外泌体在心梗后心肌修复中的作用和调控机制，发现外泌体来源miR-125b在心梗后心肌修复中有重要的调控作用。同时，我们构建富含miR-125b的靶向外泌体定位至心肌缺血部位，起到显著的抗心肌凋亡作用与促心梗后心功能恢复的能力。此外我们还证明，血浆外泌体来源的miR-125a-5p可通过ECE1/AKT/eNOS通路调控侧支循环的形成；脐血源性外泌体来源的ANRIL可通过Akt/eNOS途径促进缺血后血管新生。我们的结果为冠心病的治疗提供了新的可能途径和理论依据。