PEDF调节内皮祖细胞抑制糖尿病创伤愈合的作用及机制

血管新生受阻是糖尿病创伤愈合的主要危险因素，内皮祖细胞（EPC）在糖尿病创伤愈合血管新生中起重要作用。最近报道 I 型、II 型糖尿病患者血中色素上皮衍生因子（PEDF）显著上调，EPC减少，我们以往研究发现 PEDF 诱导血管内皮细胞凋亡，但PEDF对EPC的调节尚待深入研究。预实验结果表明腹腔注射PEDF显著减缓小鼠的伤口愈合并降低血中EPC,由此我们的科学假设是糖尿病情况下上调的PEDF通过抑制EPC阻碍血管新生、抑制创伤愈合。本研究拟设计下列内容：①建立糖尿病创伤动物模型，检测血清和主要代谢器官中PEDF是否高表达及创伤愈合功能变化，拮抗PEDF可否改善创伤愈合；②明确PEDF抑制EPC释放、伤口归巢及向内皮细胞分化等功能的作用和机制；③观察高糖及其终产物上调PEDF 表达的作用及机制。旨在明确糖尿病创伤修复过程中血管新生能力下降的原因和关键调控分子，为治疗糖尿病足提供干预新靶点。

Impaired neovascularization is the major risk factor for diabetic wound healing， endothelial progenitor cells(EPCs) play vital role in vasculogenesis of wound healing. Recent studies have reported that the plasma pigment epithelium-derived factor(PEDF) of type I and type II diabetic patients was significantly elevated, while circulating EPCs numbers decreased . Our previous study found that PEDF induced endothelial cell apoptosis, whereas the effect of PEDF on EPCs has less reports. Our preliminary data showed that intraperitoneal injection of PEDF significantly slowed down the wound healing process and reduced the circulating EPCs numbers in normal mice. Thus, we speculate that high PEDF level in case of diabetes decreases peripheral neovascularization and impairs wound healing by down-regulating EPCs. This study was aimed to illustrate the role and mechanism of PEDF in diabetic would healing. Firstly, we will investigate whether PEDF in serum and the main metabolic organs were increased in diabetic wound healing mice model, then the possibility of improving wound healing when antagonizing PEDF. Secondly, we will identify the effects and the underlying mechanism of PEDF on the mobilization, homing and differentiation of EPCs. Finally, we will elucidate how PEDF expression is regualted by high glucose and AGEs. Overall, this study will elucidate the possible reason of neovascularization impairment in diabetic foot ulcer and identify the key molecules, therefore provides novel target molecules for the treatment of diabetic foot ulcer.