树突状细胞来源exosomes调控内皮祖细胞促进动脉粥样硬化外膜滋养血管形成的机制研究

Adventitial vasa vasorum participates in progression and regression of atherosclerosis as tunnels for transportation of inflammative cells and lipids under local inflammatory microenvironment, while endothelial progenitor cells (EPCs) play a key role of vasa vasorum formation. Data from our previous studies showed that dendritic cells’ exosomes (DEXs) could significantly inhibit atherosclerotic lesions progression, which accompanied with loss of adventitial vasa vasorum around the atherosclerotic arteries. Furthermore DEXs were shown to modulate the in vivo activity of EPCs by other studies. Based on these, a hypothesis was proposed that DEXs might modulate EPCs’ in vivo function, which could promote formation of adventital vasa vasorum around the involved atherosclerotic arteries and eventually lead to un-stabilization and remodeling of arteries. In order to prove it, EPCs were firstly cocultured with dendritic cells after different pretreatments and investigated change of in vitro and in vivo function, and then the involved mechanisms were explored with miRNA arrays and siRNA, et al. At last the influence of transfusion of different pretreated EPCs in plaque burden and adventital vasa vasorum was investigated among LDLR knockout mice fed with high fat diet. Data of our experiments will help to uncover mechanism of pathological arterial remodeling involved with DEXs modulated-EPCs, and furthermore provide potential novel strategies and targets for clinical intervention.

血管外膜滋养血管是局部微环境炎症免疫细胞和脂质输送的重要通道，参与动脉粥样硬化（AS）斑块的进展或消退，但其形成的具体调控机制不明。现已知内皮祖细胞(EPCs)定向迁移分化是调控滋养血管形成的关键，前期研究发现：树突状细胞来源exosomes（DEXs）可显著抑制斑块进展，伴随外膜滋养血管减少，结合文献报道DEXs参与EPCs在体功能的调节，据此，提出“DEXs调节EPCs促进动脉粥样硬化外膜滋养血管形成，进而导致血管失稳态和重构”的假说。为验证该假说，拟首先在体外观察不同处理激活后的树突状细胞对与之非接触共培养的EPCs功能的影响，并采用miRNA芯片和siRNA等技术对可能的信号通路和关键调控因子进行筛选并验证；最后在LDLR-/-高脂喂养小鼠中，回输不同预处理的EPCs，观察对斑块负荷及外膜滋养血管的影响。本课题的深入研究将有利于揭示病理性血管重构的机制并为临床干预提供新思路和靶点。

血管外膜滋养血管是局部微环境炎症免疫细胞和脂质输送的重要通道，参与动脉粥样硬化（AS）斑块的进展或消退，但其形成的具体调控机制不明。现已知内皮祖细胞(EPCs)定向迁移分化是调控滋养血管形成的关键，提出“DEXs调节EPCs促进动脉粥样硬化外膜滋养血管形成，进而导致血管失稳态和重构”的假说。我们通过临床观察性研究发现：合并有颈动脉动脉粥样硬化的冠心病患者其外周循环内皮祖细胞水平显著降低且伴功能异常，同时循环中树突状细胞来源exosomes水平显著升高，并与冠心病严重程度Genisi积分正相关；随后在LDLR-/-高脂喂养小鼠中，给予树突状细胞来源exosomes进行干预，发现可显著降低斑块负荷，其相关机制可能与调节机体免疫密切相关。本研究揭示了来自激活树突状细胞的exosomes可显著抑制动脉粥样硬化斑块进展，伴随外膜滋养血管密度的显著降低，体外实验提示该作用与其对内皮祖细胞的功能调节密切相关。本课题的深入研究将有利于揭示病理性血管重构的机制并为临床干预提供新思路和靶点。