S1PR1和VEGF受体在急性心肌梗死后血管新生中的交互作用

项目名称： S1PR1和VEGF受体在急性心肌梗死后血管新生中的交互作用

项目编号： No.81470472

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张林

作者单位： 同济大学

项目金额： 73万元

中文摘要： 1-磷酸鞘氨醇 (S1P)是一种脂质活性分子，S1P受体1型（S1PR1）和VEGF受体（VEGFRs）有交互作用，两者有时序性地控制着血管新生和成熟。本课题组新近发现：阻断S1PR1会抑制心肌梗死后的血管新生，说明S1PR1可能对心梗后血管新生有重要影响，其机制可能与VEGFRs密切相关。本研究拟采用血管内皮细胞S1PR1基因缺失小鼠，制作急性心梗模型，运用免疫组化、microSPECT和心超评估S1PR1对心梗后血管新生、心肌存活和心功能的影响；阻断或激活S1PR1信号, 同时在缺血心肌处过表达VEGF或抑制VEGFRs，研究两者在心梗后血管新生中的交互作用；利用蛋白芯片解析S1PR1和VEGFRs交互作用所涉及的信号通路；探索VEGF基因治疗有时序性地辅以S1PR1调控剂来促进心梗后血管新生的方法。本项目将为阐明心梗后血管新生的机制和探索有效的促进血管新生的新方法提供重要的实验依据。

中文关键词： 急性心肌梗死；血管新生；1-磷酸鞘氨醇；血管内皮生长因子

英文摘要： Acute myocardial infarction (MI) is a major public health problem in the 21st century. Pro-angiogenic therapy is essential to rescue ischemic myocardium after MI, and to prevent the transition to heart failure. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid metabolite, tightly regulates cardiovascular functions via its receptors. Our previous data show that the ventricles express S1P receptor 1 (S1PR1), which plays an essential role in cardiovascular system. Recent investigations suggest that a transactive and complementary relationship between S1PR1 and vascular endothelial growth factor receptors (VEGFRs) signaling, which is known as a key pro-angiogenic factor. More importantly,the crosstalk between S1PR1 and VEGFRs signaling sequentially controls angiogenesis under physiological conditions. Under pathophysiologic conditions, e.g. post-MI, VEGFRs signaling is essential for angiogenesis in ischemic myocardium; however, the effect of S1PR1 on post-MI angiogenesis is unknown. Our preliminary results reveal that S1PR1 antagonist, W146, inhibits post-MI angiogenesis. Hence, we hypothesize that S1PR1 signaling is involved in regulating post-MI angiogenesis, and that the crosstalk between S1PR1 and VEGFRs signaling may contribute to angiogenesis in ischemic myocardium. To clarify this, we plan to induce acute MI in vascular endothelial specific S1PR1-deficient mice. We will apply histological analyses， microSPECT/CT, and cardiovascular ultrasound to examine the effect of S1PR1 on cardiac angiogenesis, cell survival and cardiac function after MI. Furthermore, we will modulate both S1PR1 and VEGFRs signaling to investigate the crosstalk between S1PR1 and VEGFRs in post-MI angiogenesis. Next, we will perform high-throughput screening of the signaling pathways of phosphorylation involved in the crosstalk between S1PR1 and VEGFRs signaling. Last, we will optimize pro-angiogenic therapy by sequentially combining VEGF gene therapy and S1PR1 modulator. Taken together, this project will reveal an unknown function of S1PR1 in post-MI angiogenesis, and uncover the mechanism how S1PR1 and VEGFRs synergistically control angiogenesis following MI. Most importantly, this project will raise a new and promising pro-angiogenic treatment of patients with acute MI.

英文关键词： acute myocardial infarction;angiogenesis;sphingosine 1-phosphate;VEGF