血管生成素-2通过活化β1整合素抑制糖尿病血管新生及伤口愈合

Impaired angiogenesis is the key to delayed wound healing in diabetes. Agiopoientin-2(Ang-2) is generally considered to be uniquely produced by endothelial cells and plays important role in revascularization and tissue reconstruction after birth. Our preliminary research showed that wound healing was delayed in diabetes along with EPC dysfunction and the up-regulation of Ang-2 in wound skin tissue. Also we found Ang-2 was synthesized by endothelial progenitor cells(EPC) and Ang-2 expression was up-regulated in diabetic EPC. It has been reported that β1 integrin was over-activated in diabetes which interacted with Ang-2/Tie system. We hypothesized that up-regulation of Ang-2 induces the over-activation ofβ1 integrin and finally leads to EPC dysfunction, impaired angiogenesis and delayed wound healing. We hope to elucidate the mechanisms of how Ang-2 regulates EPC function throughβ1 integrin and to provide theory and experience support for the cure of delayed wound healing in diabetes.

血管新生障碍是糖尿病伤口愈合延迟的关键病因。血管生成素-2(Ang-2)主要由内皮细胞合成，参与出生后血管再生和组织重构。我们的前期研究表明糖尿病小鼠伤口愈合减慢，伴随皮肤组织中Ang-2表达增高；同时首次发现骨髓来源内皮祖细胞(EPC)能表达Ang-2，且糖尿病EPC存在血管新生功能障碍同时伴有Ang-2表达上调，因此糖尿病时Ang-2过度表达可能与EPC功能障碍、伤口愈合延迟密切相关。有研究报道糖尿病时Ang-2表达增高可能导致内皮细胞β1整合素活化增加，以及内皮细胞功能障碍。我们假设糖尿病时Ang-2高表达通过使β1整合素过度活化，引起内皮祖细胞功能障碍，血管新生受损，最终导致伤口愈合延迟。希望通过本项目研究，可以阐明Ang-2调节β1整合素活化及内皮祖细胞功能的机制，从而为糖尿病伤口愈合延迟的治疗提供理论依据与实验支持。

本课题研究发现，糖尿病小鼠伤口愈合延迟，伴随伤口皮肤组织及骨髓来源EPC中Ang-2表达增高，同时伴有血管新生受损及EPC功能障碍，以及β1整合素活化增加。进一步的研究表明，过多Ang-2抑制糖尿病EPC功能、皮肤血管新生及伤口愈合，而体内抑制Ang-2则能通过减少β1整合素活化而改善糖尿病EPC功能、血管新生及伤口愈合。同时体外细胞培养实验证实，过高水平Ang-2能够抑制非糖尿病及糖尿病小鼠EPC功能，而抑制Ang-2可改善糖尿病EPC功能，减少β1整合素活化。