血管内皮细胞中G蛋白偶联受体4与血管内皮生长因子受体2之间crosstalk的发生机制研究

项目名称： 血管内皮细胞中G蛋白偶联受体4与血管内皮生长因子受体2之间crosstalk的发生机制研究

项目编号： No.31201060

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 遗传学与生物信息学、细胞生物学

项目作者： 任娟

作者单位： 西安交通大学

项目金额： 23万元

中文摘要： 细胞膜上不同受体间可发生Crosstalk，从而使细胞整合不同的信号和通路。我们前期首次发现血管内皮细胞上鞘氨醇磷酸胆碱SPC的受体GPR4与血管内皮生长因子受体2间存在crosstalk。SPC作用于GPR4后促进内皮细胞的增殖、血管生成、并激活ERK和AKT，而应用VEGFR2抑制剂：VEGFR2特异性抑制剂和酪氨酸激酶抑制剂均可阻断SPC/GPR4的作用，即GPR4作用依赖于VEGFR2，说明GPR4与VEGFR2间存在Crosstalk。我们推测有三种发生机制：SPC作用于GPR4后①刺激VEGF的产生，分泌致胞外的VEGF激活VEGFR2，再激活下游信号；②GPR4与VEGFR2间形成复体complex，使VEGFR2活化。③SPC/GPR4直接作用于VEGFR2磷酸化位点使其活化。本项目拟在血管内皮细胞中研究其机制，对了解心血管疾病和肿瘤的发展有重要意义。目前尚未见到相关报道。

中文关键词： GPR4；血管内皮生长因子受体2；相互作用；SPC；血管生成

英文摘要： Receptor Crosstalks occur among different cell membrane receptors. These receptors crosstalks allow cells to integrate different cellular signals and pathways in order to carry out the biological regulations. Our previous study firstly found that, there exists crosstalk between SPC receptor, G protein coupled receptor 4(GPR4), and receptor 2 of vascular endothelial growth factor(VEGF). When SPC bound to GPR4, the proliferation and tube formation of vascular endothelial cell were stimulated. ERK and AKT were also activated. But to our surprise, when VEGF R2 inhibitors including VEGFR2 specific inhibitor and tyrosine kinase inhibitor were applied, the SPC effect was significantly blocked by VEGFR2 inhibitors. In another word, the effect of SPC/GPR4 on vascular endothelial cells is dependent on VEGF R2. That means, there exist crosstalk between GPR4 and VEGF R2. We speculate there are three possible mechanisms of this crosstalk. The first possible mechanism is the sequential model. The production and secretion of VEGF may be induced after SPC binds to GPR4. Extracellular VEGF then activates VEGF R2 and its downstream signaling pathways; The second possible mechanism is the integration model. The complex of GPR4 and VEGF R2 may form after SPC binds to GPR4. VEGF R2 is consequently activated; The third possible mecha

英文关键词： G-protein coupled receptor 4；Vascular endothelial growth factor receptor 2；Crosstalk；Sphingosylphosphorylcholine；Angiogenesis