活性氧强化β-arrestin-2调控内皮型一氧化氮合酶活化在门静脉高压症内脏动脉扩张中的作用机制

Hyperdynamic circulation caused by dilatation of visceral artery in portal hypertension (PHT) is the leading reason of death in esophageal varices bleeding.High expression of β-arrestin-2 in visceral artery was found in our previous study for the first time, in the condition of high level of ROS with PHT. We also found that this phenomenon strengthened the combination of β-arrestin-2 with bradykinin receptors and eNOS, while weaken this combination ability of caveolae(caveolin-1, CAV-1) at the same time. Further it can stimulate eNOS activation pathway, via ERK signal pathway, lead to an elevation of NO and inhibit tTG expression and activity. Our study hypothesize that due to ROS up-regulation in PHT, G protein-coupled receptor (GPCR) recruits inactive eNOS after combinated with corresponding ligand and enter the cytoplasm, which is from caveolae(caveolin-1)-mediated to β-arrestin-2/clathrin-mediated. The eNOS is actived via ERK signal, leading to elevating NO synthesis and release. NO increasement can inhibit RhoA/ROCK pathway as well as tTG expression and activity, by which vascular wall become thinner to maintain the dilation of visceral artery.This project aims to benefit for the research of novel antioxidant drugs for relieving the dilatation of visceral artery and hyperdynamic circulation.

门静脉高压症（PHT）内脏动脉扩张引起的高动力循环是食管胃底曲张静脉破裂出血导致死亡的首要原因。前期研究我们首次发现，PHT时ROS水平升高，引起内脏动脉β-arrestin-2高表达。预实验发现该现象弱化了原先小窝蛋白-1（CAV-1）与缓激肽受体和eNOS的结合，强化了β-arrestin-2结合缓激肽受体和eNOS的能力，经ERK通路活化eNOS，导致NO增多,进而抑制tTG的表达和活性。本研究首次推测：PHT中，由于活性氧水平增高，NO激动剂与相应的G蛋白偶联受体结合后，募集无活性eNOS由原先小凹（CAV-1）介导转换为β-arrestin-2/网格蛋白介导的形式入胞，经ERK信号通路活化eNOS，NO合成和释放增加，进而抑制RhoA/ROCK信号通路，抑制tTG的表达和活性，引起动脉管壁变薄，维持内脏动脉扩张。本课题有助于开发新的抗氧化药物，治疗内脏动脉扩张和高动力循环。

门静脉高压症（PHT）内脏动脉扩张引起的高动力循环是食管胃底曲张静脉破裂出血导致死亡的首要原因。我们研究发现，在PHT状态下，除了原先小窝蛋白（CAV-1）与缓激肽受体和eNOS的结合外，由于ROS水平升高，NO激动剂与相应的G蛋白偶联受体结合后，β-arrestin-2/网格蛋白募集游离的无活性eNOS，经PI3K/Akt通路活化eNOS，导致NO增多,进而促进血管平滑肌舒张,维持内脏动脉扩张。本课题研究结果在肝硬化门静脉高压症发病机制研究上有所突破，将为抗氧化剂治疗肝硬化门静脉高压症机理的阐明提供理论依据；根据相应成果开发研究相应药物，将对肝硬化和门静脉高压症的预防和治疗带来革命性的变化，具有重大的社会效益和经济效益。