EETs调控NOX-ROS-caveolin-1通路在肝硬化门静脉高压症中的作用机制

Increased intrahepatic vascular resistance and splanchnic artery dilatation are two of major pathological causes in cirrhotic portal hypertension (PHT). We found that the expression of epoxyeicosatrienoic acids (EETs), compared with normal liver tissue, decreased in cirrhotic liver tissue , while that of cirrhotic peripheral vessels increased, compared with normal peripheral vessels. These data indirectly reflected abnormal changes of EETs in portal hypertension, but the effects or mechanisms of EETs on intrahepatic vascular resistance and splanchnic vasodilatation were unclear in liver cirrhosis with portal hypertension. This study focused on the role of EETs in intrahepatic vascular resistance and splanchnic vasodilation in vivo and vitro. We will explore how EETs regulate eNOS subcellular localization through modulation of NOX-ROS-caveolin-1 signal pathway, to reverse the deterioration of intrahepatic vascular resistance and splanchnic artery dilatation based on vascular remodeling. Moreover, this study will reveal the role and mechanisms of EETs in the occurrence and development of portal hypertension, to promote the clinical treatment of portal hypertension targeting EETs.

肝内血管阻力增加和内脏动脉扩张是肝硬化门静脉高压症（PHT）两大主要病因。前期研究发现肝硬化PHT时环氧二十碳三烯酸（epoxyeicosatrienoic acids, EETs）在肝内外出现异常改变，EETs在肝内明显降低，而在肠系膜动脉内水平则高于正常。但EETs的这种变化对肝硬化门静脉高压症的影响和机制目前尚不清楚。本课题通过体内外实验着重研究EETs如何通过NOX-ROS-caveolin-1信号通路调控eNOS亚细胞定位从而对PHT肝内血管阻力和内脏血管扩张产生影响，进而阐明EETs在肝内外在PHT发生、发展中的作用及机制，以此推动EETs为靶点的临床治疗。

肝内血管阻力增加和内脏动脉扩张是肝硬化门静脉高压症（PHT）两大主要病因。前期研究发现肝硬化PHT时环氧二十碳三烯酸（epoxyeicosatrienoic acids, EETs）在肝内外出现异常改变，EETs在肝内明显降低，而在肠系膜动脉内水平则高于正常。但EETs的这种变化对肝硬化门静脉高压症的影响和机制目前尚不清楚。本课题通过体内外实验，验证了肝窦内皮细胞中受sEH调控的EETs可通过抑制NOX活性，从而抑制ROS的产生，减弱c-src依赖的CAV-1磷酸化，减少“CAV-1-eNOS”结合，增强eNOS入胞磷酸化，NO合成、释放增加，肝内血管阻力降低；在内脏血管内皮细胞中，增加EETs水平，抑制NOX4来源的H2O2产生，从而抑制β-arrestin-2的表达，诱导eNOS与CAV-1结合于胞质膜，回到非活化状态，缓解NO介导的内脏动脉管壁重构，增强血管收缩，从而改善高动力循环。门静脉高压症大鼠中，肠系膜上动脉在发生功能性的血管扩张的同时，在其周围并行存在大量的肠系膜淋巴管增生。