胰高血糖素样肽-1通过内质网应激调节内皮祖细胞线粒体自噬促进糖尿病下肢缺血后血管新生的机制研究

糖尿病周围动脉病变（DPAD）是糖尿病最常见并发症之一，也是非创伤性截肢的首要原因，治疗药物有限且预后不良。恢复高糖环境下内皮祖细胞（EPCs）促血管新生功能是解决下肢动脉缺血缺氧的根本措施。团队前期发现胰高血糖素样肽-1(GLP-1)改善糖尿病小鼠缺血下肢的血流灌注及促毛细血管新生；抑制高糖诱导的线粒体自噬，缓解胞浆内和线粒体内钙紊乱，恢复内皮细胞功能产NO能力。由此提出：GLP-1通过调控内质网钙流向缓解高糖下线粒体自噬，恢复EPCs血管新生能力。本项目将以db/db、STZ诱导及条件性敲除糖尿病小鼠下肢缺血模型和高糖作用下EPCs为研究对象，通过体内注射和培养基中添加GLP-1的方式，观察GLP-1是否通过影响内质网应激的发生和钙的稳态调控线粒体自噬，进而改善EPCs促血管新生能力。本项目旨在阐明GLP-1促进高糖环境下血管新生的新机制，为DPAD治疗提供新思路和新靶点。

Diabetic Peripheral Arterial Disease (DPAD) is one of the most common chronic complications of diabetes mellitus, and it is also the leading cause of non-traumatic amputation with poor treatment and prognosis. Restoring the pro-angiogenic function of endothelial progenitor cells (EPCs) in high glucose is a fundamental measure to solve the problem of lower extremity artery ischemia and hypoxia. Our previous study found that glucagon-like peptide-1 (GLP-1) could improve blood perfusion and angiogenesis in ischemic lower extremity of diabetic mice. Meanwhile, GLP-1 inhibited mitophagy induced by high glucose, alleviated intracytoplasmic and mitochondrial calcium disorders and restored NO secretion. Based on previous results, we proposed a hypothesis: GLP-1 alleviates mitophagy in high glucose and restores the angiogenesis of EPCs by regulating Ca2+ flow in the endoplasmic reticulum. The lower extremities ischemia of type 1 and type 2 diabetic mice, conditional knockout mice and EPCs under high glucose stimulation were studied in this project. To observe whether GLP-1 regulates mitophagy by ER stress and Ca2+ homeostasis to improve the angiogenesis of EPCs, GLP-1 is injected in vivo or added to culture medium. This project aims to elucidate the new mechanism of GLP-1 promoting angiogenesis in high glucose, and provide new ideas and new targets for DPAD therapy.