PEDF在糖尿病血管内皮损伤中的关键作用及机制

血管病变是糖尿病患者致残、致死的主要原因。内皮损伤是启动血管病变的早期关键步骤，涉及内皮细胞结构功能异常及和血小板、巨噬细胞的相互作用，但关键调控分子及机制尚不明确。我们以往发现：糖尿病患者血浆PEDF升高，在伴有血管并发症的患者中PEDF升高更显著；升高的PEDF抑制内皮祖细胞的释放和内皮修复功能；预实验结果显示拮抗或敲除PEDF改善糖尿病内皮舒张功能、降低糖尿病小鼠活化血小板的数量。以上研究提示异常升高的PEDF可能是介导糖尿病内皮损伤的关键分子。本项目设计如下：①建立糖尿病和PEDF转基因/敲除鼠等模型，进一步明确PEDF在糖尿病内皮损伤中的关键作用；②明确PEDF是否通过抑制Src/caveolin-1/eNOS信号通路影响血管内皮舒张功能；③明确PEDF是否调控内皮细胞分泌WP小体激活血小板加剧内皮损伤。旨在阐明PEDF的关键作用和机制，为防治糖尿病血管病变提供新思路和干预靶点。

Vascular disease is the major cause of disability and mortality in patients with diabetes mellitus. Endothelial dysfunction is an early event and the key step for the onset of vascular disease, including the abnormality of structures and functions of endothelial cells and the interaction between endothelial cell and other vascular cells such as platelets and macrophages, but the precise mechanism and signaling pathway involved in mediating endothelial dysfunctionin in diabetes remain unclear. Our previous studies revealed that plasma PEDF was increased in diabetic patients, and the increase of plasma PEDF was more prominent in patients with vascular complications. Elevated PEDF suppressed the mobilization of endothelial progenitor cells (EPCs) and repair of endothelium in the diabetic mice. Our preliminary data has demonstrated that either blockade with antibody or genetic deletion of PEDF ameliorates vasodilation and re-endothelialization, and reduces the platelet aggregation in diabetic mouse models. These results suggest that PEDF may play a pivotal role in mediating the endothelial dysfunction in diabetes, which ultimately leads to vascular disease. The details were designed in the research project: 1. The PEDF overexpressing/knockout mice with diabetes will be established to investigate the crucial role of PEDF on endothelial dysfunction in diabetes. 2. The mechanism by which PEDF regulates endothelial dysfunction in diabetes will be addressed 1.)Whether PEDF regulates vasodilation function via inhibiting Src/caveolin-1/eNOS pathway in endothelial cells. 2.) Whether PEDF promotes the platelet aggregation via regulating Weibel-Palade body exocytosis of endothelial cells, in which containing the platelet activating factors. 3. Exploring the mechanism of PEDF up-regulation in diabetes. The purpose of the present study is to identify the crucial role and the underlying mechanism of PEDF in mediating the vascular endothelial dysfunction in diabetes. This study will provide a novel therapeutic target for the vascular complications of diabetes.