CGRP/RAMP1轴抑制血管外膜炎症反应保护高血压血管损伤的机制研究

The nervous system is closely related to the cardiovascular system. Neuropeptides secreted by nerve fibers are important endogenous active substances that regulate various cardiovascular diseases. Our previous study found that the extravascular distribution of calcitonin gene-related peptide (CGRP)-positive nerves and confirmed that the adventitial inflammation is involved in vascular remodeling, but whether CGRP is involved in this process remains unclear. Pre-experiment found that in angiotensin II-induced hypertension model, exogenous CGRP was given to lower blood pressure and improve vascular wall thickening and adventitial inflammation. Meanwhile, adventitial fibroblasts were found to express CGRP receptor-Receptor activity modifying protein 1 (RAMP1). Therefore, this project hypothesized that the activation of CGRP/RAMP1 signal on the adventitial fibroblasts is participated in the regulation of the adventitial inflammation and blood pressure. On this basis, the project constructed a model of hypertension to study 1) the regulation of CGRP and its receptors in blood pressure regulation and vascular adventitial inflammation; 2) Adventitial fibroblast-specific RAMP1 knockout aggravates vascular remodeling mediated by adventitial inflammation; 3) the mechanism by which CGRP improves adventitial inflammation through RAMP1. The implementation of this project will provide a new theoretical basis for the research of new drugs targeting the CGRP/RAMP1 axis.

神经系统与心血管系统密切相关，神经纤维分泌神经肽是调控各种心血管疾病的重要内源性活性物质。我们前期研究发现血管外膜分布降钙素基因相关肽（CGRP）阳性神经，并证实血管外膜炎症反应参与血管重塑，然而CGRP是否参与此过程仍不清楚。预实验发现在血管紧张素II诱导高血压模型上，给予外源CGRP降低血压并改善血管壁增厚及外膜炎症反应；同时发现外膜成纤维细胞表达CGRP受体，即受体活性修饰蛋白（RAMP1）。因此本项目假设：外膜成纤维细胞上的CGRP/RAMP1信号激活参与外膜炎症反应及血压的调节。本项目在此基础上，构建高血压模型，研究1）CGRP及其受体在血压调节及血管外膜炎症反应中的调控作用；2）外膜成纤维细胞特异性RAMP1敲除加重血管外膜炎症反应介导的血管重塑；3）CGRP通过RAMP1改善血管炎症反应的作用机制。本项目的实施将有助于以CGRP/RAMP1轴为靶点的新药研究提供新的理论依据。

炎症反应尤其是巨噬细胞激活在高血压及其血管损伤的发生发展中发挥重要作用，降钙素基因相关肽（calcitonin gene related peptide，CGRP）是感觉神经释放的重要肽类物质，通过其受体——受体活化修饰蛋白1（Receptor activity modifying protein 1，RAMP1）发挥生物学效应，但CGRP/RAMP1是否参与调控高血压血管炎症反应尚不清楚。本项目基本按计划进行：体内给予CGRP改善AngII诱导的小鼠高血压，抑制血管重构和炎症反应；证实巨噬细胞RAMP 1缺失促进血管紧张素II（Ang II）诱导小鼠血管损伤的发生并探讨其下游的机制。以上研究为防治腹主动脉瘤的发生提供新的治疗策略及干预靶点提供了理论依据。