内皮祖细胞来源的前列腺素E2在肾移植中调节血管新生过程的作用机制研究

The blood flow blocking during kidney transplantation often results in renal ischemic injury. In this process, endothelial cells and endothelial progenitor cells (EPC) are activated to participate in angiogenesis, which will be of great help in tissue regeneration. Prostaglandin E2 (PGE2) is a kind of metabolites of arachidonic acid, and is widely distributed in human. It is recognized as a mediator of inflammation, ischemia and tumorigenesis. PGE2 is also known to activate angiogenesis and regulate other physiological or pathophysiological process by binding to four receptors, named EP1, EP2, EP3 and EP4. Our preliminary data indicated that the EPC from patients’ peripheral blood after kidney transplantation, regulated the tube formation capacity and other biological functions of endothelial cells by paracrine PGE2, a kind of arachidonic acid metabolites. In addition, the expression of Transcription Krüppel-like factor 2 (KLF2) was increased during this process. KLF2 protein participates in endothelial function protection and angiogenesis regulating. Therefore, in this study we will demonstrate the regulation of EPC of kidney transplantation patients to endothelial cells using techniques of metabonomics, cell biology and molecular biology. The aim of this study is to explore the effects of EPC from peripheral blood after kidney transplantation and to reveal the molecular mechanisms of angiogenesis.

肾移植术中肾动脉血流被阻断，血管内皮细胞和外周血中血管内皮祖细胞均可被激活，直接或间接参与血管新生过程从而改善肾脏的缺血性损伤。前列腺素E2（PGE2）在机体内广泛存在，是一类在炎症、缺血和肿瘤等应激状态局部大量合成和分泌的花生四烯酸代谢产物，通过与其四种受体的结合，调节血管新生、炎症等生理、病生理过程。本课题前期实验结果提示，肾移植病人外周血来源的内皮祖细胞可以产生大量PGE2，以旁分泌的作用方式影响血管内皮细胞的成血管功能。在此过程中伴随着内皮细胞中转录因子KLF2表达的增加。KLF2在维持内皮细胞正常功能、调节血管新生过程中发挥重要的作用。因此，本研究拟利用代谢组学、细胞生物学、分子生物学等多种技术手段，在肾移植病中探讨内皮祖细胞对内皮细胞功能的调控作用，以求深入挖掘循环血中内皮祖细胞间接影响血管新生过程的分子机制。

肾移植术中需阻断动脉血流的血液供应，使得肾脏发生缺血和缺氧损伤，移植术后，利用多种手段增加损伤组织中新生血管形成，及时恢复缺血组织中的血供，可减轻许多病生理过程。本研究中，利用质谱技术、分子生物学技术、细胞生物学技术、获得性功能实验和缺失性功能实验等，发现了肾移植术后外周血中血管内皮祖细胞被激活，释放出大量花生四烯酸代谢产物前列腺素E2（PGE2），内皮祖细胞释放出的PGE2，可以通过与血管内皮细胞的PGE2受体EP2结合，激活血管内皮细胞中蛋白激酶AMPK，进一步增加转录因子KLF2的表达，在转录水平增强血管内皮的成血管能力。本课题探讨了外周血来源内皮祖细胞代谢并分泌出的PGE2对内皮细胞的调控作用及其机制，为肾移植术后增加新生血管数目、及时恢复血供、增强受损组织修复提供了可靠的实验依据与治疗思路。

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