青年项目中申请人阐述了Meprinα介导巨噬细胞氧化应激并促进动脉粥样硬化斑块形成的作用，但Meprinα对粥样斑块进展的影响及其机制尚未探讨。研究揭示血管外膜的滋养血管网扩张促进粥样斑块生长，而成纤维细胞激活调节滋养血管网扩张，但其机制尚未阐明。申请人在前期工作中发现Meprinα促进滋养血管网扩张，并介导成纤维细胞氧化应激调节成纤维细胞功能。据此，我们推断Meprinα通过氧化应激介导成纤维细胞激活，诱导滋养血管网扩张最终促进动脉粥样硬化斑块进展。本课题拟制备Meprinα—/—/ApoE—/—和ApoE—/—小鼠斑块进展动物模型，建立成纤维细胞和滋养血管内皮细胞共培养体系，应用MicroCT、细胞共培养、分子克隆、激光共聚焦等技术，从整体-细胞层次证明我们的假说，本研究的顺利实施可为临床延缓动脉粥样硬化疾病进展提供新药靶点和理论基础。

The investigator has demonstrated Meprinα promoted the formation of Atherosclerotic plaque through induction of oxidative stress in Macrophages in the National Natural Science Foundation of China-Youth Project, but the effect of Meprinα on atherosclerotic plaque progression has not been explored. Studies have revealed that the growth of Atherosclerotic plaque was directly induced by vasa vasorum expansion in vascular adventitial, and activation of Fibroblasts, the most abundant cells in adventitial, plays a key role in regulation of vasa vasorum expansion, but its mechanism has not been elucidated. The investigator also found that Meprinα promoted vasa vasorum expansion, mediated oxidative stress in adventitial Fibroblasts and regulated the fuction of Fibroblasts. We speculate that Meprinα may activate Fibroblasts via induction of oxidative stress, and then induce vasa vasorum expansion which contribute to atheroma progression. In this project, we prepare animal model of advanced plaques using Meprinα-/-/ApoE-/- mice and ApoE-/- mice, and establish a co-culture system of vascular adventitia FCs and vasa vasorum endothelial cells. Using the MicroCT technology, co-culture system, molecular cloning, and confocal laser technology, we want to confirm our hypothesis in vivo and ex vivo level. The project, if implemented smoothly, will provide a new target and a theoretical basis for retarding atherosclerosis. ..