RhoA/ROCK通路参与阿帕替尼治疗乳腺癌致高血压的相关机制及防治研究

靶向治疗极大地降低了癌症的死亡率，高血压是抗血管新生性靶向药物的主要不良反应之一。由于其机制主要与血管内皮功能异常，导致小血管阻力增高有关，该类高血压的防治不同于普通高血压。既往研究证实RhoA/ROCK通路参与内皮细胞功能异常相关高血压的发生，抑制该通路可阻断上述作用。本项目拟应用乳腺癌造模小鼠及RhoA/ROCK通路关键基因LARG基因敲除小鼠，探索RhoA/ROCK通路是否为阿帕替尼治疗乳腺癌所致高血压及其靶器官损害的可能机制，并研究ROCK通路抑制剂是否具有治疗作用。采用多种方法分析阿帕替尼干预后主动脉及肠系膜动脉RhoA/ROCK通路蛋白表达及相应mRNA水平，比较血压及血流动力学指标,测定内皮功能及血管力学性能指标及主动脉中膜与左心室纤连蛋白、胶原蛋白水平，以评估血管僵硬度及心肌纤维化程度，比较各组血管、肾脏组织学差异。以期通过此研究对该类型高血压的防治提供依据。

Hypertension is one of the main adverse effects of anti-angiogenic tumor drug apatinib, which is also one of the main factors affecting its application. As its mechanism is mainly related to vascular endothelial dysfunction, which leads to increased resistance of small blood vessels, the prevention and treatment of this type of hypertension is different from primary hypertension. Previous studies have confirmed that the RhoA/ROCK pathway is involved in the pathogenesis of hypertension related to vascular endothelial dysfunction.The purpose of this project is to explore whether the RhoA/ROCK pathway participates the pathogenesis of hypertension induced by apatinib, using breast cancer model mice and RhoA/ROCK pathway key gene LARG knockout mice. The project also aims to determine whether inhibitors of Rho/ROCK pathway have a preventive and therapeutic effect on this type of hypertension and its related organ damage. The blood pressure and hemodynamic parameters in each group will be monitored. Western blot, PCR and immunohistochemistry were used to determine the expression of RhoA/ROCK pathway protein and corresponding mRNA in aorta and mesentery after intervention with apatinib. Blood pressure levels and hemodynamic parameters will be monitored. To assess vascular stiffness and myocardial fibrosis, the endothelial function and vascular mechanics, levels of fibronectin, collagen Iα1 (COL1α1) and collagen IIIα1 (COL3α1) in aorta media and myocardium will be detected. Through the above methods, this study intends to provide experimental evidences for the prevention and treatment of this type of hypertension.