GLP-1通过调控线粒体自噬改善EPCs合成NO促进糖尿病缺血下肢血管新生的作用和机制

糖尿病周围动脉病变(DPAD)发病率高且危害严重，恢复内皮祖细胞（EPCs）促血管新生能力改善缺血是主要治疗策略。本团队前期发现GLP-1具有独立降糖作用之外的促治疗性血管新生的作用，但机制不明。本研究假设：GLP-1通过调控线粒体自噬，清除高糖引起的过量ROS，逆转eNOS的脱偶联分泌NO，动员EPCs从骨髓迁移到缺血部位促血管新生。本项目拟构建多种在体和离体模型，利用基因敲除，siRNA，骨髓移植，免疫共沉淀，透射电镜，流式细胞分析和Seashorse等技术，确证GLP-1促进EPCs血管新生改善下肢缺血的新功能，阐明GLP-1通过调控线粒体自噬和稳态，恢复高糖环境EPCs分泌NO的新机制，为DPAD的治疗提供新的思路和靶点。

Diabetic Peripheral Arterial Disease (DPAD) has attracted widespread attention in all population and has a predominant health threat worldwide. The migratory function of Endothelial Progenitor Cells (EPCs) is to promote angiogenesis. Previous studies in our group has shown that GLP-1 has a role in promoting therapeutic angiogenesis after ischemia, but the mechanism is unclear. In this study, we hypothesize that GLP-1 might induce mitophagy to eliminate excess ROS induced by high glucose treatment, reverse the uncoupling of NO from eNOS and mobilized EPCs to migrate from bone marrow to ischemia to promote angiogenesis. Constructing in vivo and in vitro models, gene knockout, RNA interference, bone marrow transplantation, co-immunoprecipitation, transmission electron microscopy, flow cytometry, seashorse and other experimental techniques were used to confirm whether GLP-1 promote EPCs to participate in the process of angiogenesis and improves limb ischemia. This study clarifies that GLP-1 might regulate mitochondrial function and increase NO secretion of EPCs, which provides a new sight for the pathogenesis and treatment of DPAD.