交感活动亢进是高血压的主要特征和发生机理，交感中枢头端延髓腹外侧区（RVLM）血管紧张素II激活G蛋白介导的AT1R信号通路是交感活动增强和血压升高的重要因素，研究提示激活β-arrestin偏向性AT1R信号通路产生与G蛋白介导的通路不同的生物学作用。因此，本项目总体目标是明确β-arrestin1偏向性信号通路在高血压心血管中枢调控中的作用和意义。在高血压和β-arrestin1基因敲除等模型上，将明确:1)β-arrestin1在高血压心血管中枢调节中的作用意义;2) β-arrestin1对高血压中枢自噬和氧化应激的作用机制;3)氧化应激调控β-arrestin1偏向性通路的作用机制；4）ACE2/Ang1-7/Mas轴对中枢β-arrestin1的作用机制。本课题对中枢β-arrestin1偏向性AT1R信号通路的心血管功能调控研究将为高血压的形成机理和防治策略提供新内容。

It has been widely accepted that sympathetic overactivity contributes to the pathophysiological processes of hypertension. Enhancement in the G protein -mediated angiotensin receptor 1 (AT1R) signaling evoked by Angiotensin II in the sympathetic center rostral ventrolateral medulla (RVLM) plays an important role in sympathoexcitation and hypertension. It is suggested that the β-arrestin-biased AT1R signaling may antagonize the harmful effect of the GPCR-mediated AT1R signaling. Therefore, this major goal of project is to determine the beneficial effect of the β-arrestin-biased AT1R signaling in the RVLM on cardiovascular dysfunction in hypertension. In animal models of hypertensive rats and β-arrestin knock-out mice, we will determine: 1) role of RVLM β-arrestin in neural control of cardiovascular activity in hypertension; 2) effect of the RVLM β-arrestin in on autophagy and oxidative stress in hypertension; 3) the effect of oxidative stress on β-arrestin in the RVLM; and 4) effect of ACE2/Ang1-7/Mas axis on the β-arrestin--biased AT1R signaling in hypertension. This project will confirm the role of β-arrestin--biased AT1R signaling in mediating the physiological and pathophysiological regulation of central cardiovascular activity, and would be helpful to our understanding of generation and protection strategy for hypertension.