前列腺素F2α受体在血管生成中的作用与机制研究

Prostaglandins (PGs) is a kind of hormone associated with promoting smooth muscle excitability and reducing blood pressure；play an important role in the cardiovascular system、reproductive system and respiratory system. Prostaglandins F2α and its receptors play an important role in vascular physiology and pathology processes, but the relationship between prostaglandin F2α and receptor and angiogenesis is not clear. Prostaglandin F is involved in regulation of vasodilation, whereas prostaglandin F also regulate the expression of VEGF which a angiogenesis related gene; the expression of prostaglandin F receptor is localized in uterus、eye and vascular smooth muscle. We found that FP expression was detected in zebrafish vascular endothelial cell, and that increased FP expression promote angiogenesis in mouse hind limb ischemia. In this research, we use FP knockout and FP overexpression in vascular endothelial cell mouse to investigate the role in vascular formation, analysis the effect in vascular endothelial cell proliferation and apoptosis, explore the potential cell signaling mechanisms. The study will be a new perspective to provide new idea for the treatment of cardiovascular-related diseases by revealing the role of prostaglandin F2α receptor in the process of angiogenesis.

前列腺素(prostaglandins, PGs)是一类具有促使平滑肌兴奋、血压降低的激素类物质；在心血管系统、生殖系统和呼吸系统等发挥重要调节作用。前列腺素F2α及其受体在血管生理和病理过程中扮演非常重要的角色，但其在血管生成中的作用尚不清楚。研究表明，前列腺素F2α能够影响血管舒张，并能调控血管内皮细胞生长因子VEGF表达；前列腺素F2α受体FP主要在子宫、眼部和血管平滑肌表达。前期研究发现，斑马鱼血管内皮细胞中能检测到FP表达；小鼠体内高表达FP能够促进下肢缺血模型中血管新生。本研究拟利用FP敲除小鼠和血管内皮细胞高表达FP转基因小鼠，分析FP在血管生成中的作用，并检测FP对血管内皮细胞增殖以及凋亡的影响，在此基础上探究FP影响血管生成的分子信号通路。本课题通过揭示前列腺素F2α受体在血管形成过程中的作用，为与血管生成相关疾病的治疗提供新思路。

血管新生是发育、炎症和缺血疾病的基础。前列腺素PGE2在病理生理血管新生中扮演重要角色，但具体机制尚不清楚。我们的研究表明，EP3受体在斑马鱼胚胎高表达。药物和基因手段敲除EP3使斑马鱼血管发育受损，小鼠视网膜生长延缓。EP3敲除通过上调Dll4基因而促进Notch活性。进一步地，EP3敲除使得β-catenin 的Ser675位点磷酸化增加，引起β-catenin核转位增加。而β-catenin 的Ser675磷酸化是由PKA介导的，EP3敲除使得PKA活性显著升高。由此，EP3活化可通过Gi降低PKA水平，减少β-catenin的入核，从而抑制Dll4的转录，降低Notch的活性，最终促进内皮细胞的出芽，增强血管新生。以上结果提示EP3可作为潜在的缺血疾病的治疗靶点。