血管成纤维细胞外泌体调控血管平滑肌细胞表型转化与高血压血管重构的分子机制

Phenotypic switch of vascular smooth muscle cells (VSMCs) and vascular remodeling play a critical role in the pathogenesis and development of hypertension. The related mechanism is a key problem that calls for immediate solution. We have found that vascular adventitial fibroblasts (VAFs) secrete exosomes, and the secreted exosomes are increased in spontaneously hypertensive rats (SHR). Preliminary studies in our lab have shown that the exosomes from VAFs stimulate phenotypic switch and proliferation and of primary VSMCs, and the exosomes from VAFs of SHR have more potent effects on phenotypic switch and proliferation than those from control rats. Based on the crucial finding, this project is designed to investigate the role and mechanism of exosomes from VAFs in the VSMCs’ phenotypic switch and vascular remodeling including the proliferation, hypertrophy, migration and fibrosis of VSMCs in hypertension. We focus on revealing the exosomes-related key targets for preventing VSMCs’ phenotypic switch and vascular remodeling in hypertension, and especially investigating the therapeutic effects of the intervention of these targets. The significance of this project is to clarify the role, mechanisms and molecular targets of exosomes from VAFs in VSMCs’ phenotypic switch and vascular remodeling in hypertension. It is hopeful to provide a novel approach and an experimental foundation for treating hypertension.

血管平滑肌细胞(VSMCs)表型转化与血管重构在高血压病的发生发展中起重要作用，其发生机制是急需解决的关键问题。我们发现血管外膜成纤维细胞（VAFs）可分泌外泌体，自发性高血压大鼠(SHR)的VAFs分泌外泌体增多，预实验显示VAFs促进血管平滑肌细胞(VSMCs)表型转化和增殖，SHR的VAFs分泌的外泌体作用更强。根据这一重要发现，本项目采用自发性高血压大鼠、原代细胞和细胞系，在整体、细胞分子和基因水平，探讨VAFs分泌的外泌体在高血压VSMCs表型转化和血管重构（包括增殖肥大、迁移和纤维化）中的作用与分子机制，特别是发现VAFs外泌体在调控VSMCs表型转化和血管重构中的关键靶点，研究干预这些关键靶点对VSMCs表型转化、血管重构和高血压的治疗作用。该研究有望阐明VAFs外泌体调控血管平滑肌细胞表型转化与高血压血管重构的分子机制与干预靶点，为防治高血压病提供新思路和奠定基础。

血管重构在高血压的发生发展和并发症形成中起重要作用。血管外膜成纤维细胞（VAFs）和血管平滑肌细胞（VSMCs）是血管重构的关键细胞成分，VAFs对VSMCs的调控作用和机制及其在高血压发病中的作用是迫切需要解决的关键问题。本项目主要探讨VAFs分泌的外泌体（细胞外囊泡）在高血压VSMCs表型转化和血管重构中的作用与分子机制，揭示VAFs分泌的外泌体在调控VSMCs表型转化和血管重构中的关键靶点，研究干预这些关键靶点对VSMCs表型转化、血管重构和高血压的治疗作用。我们发现VAFs可分泌外泌体，调节VSMCs表型转换。自发性高血压大鼠（SHR）VAFs产生的外泌体促进VSMCs表型转换、增殖和迁移。SHR的VAFs产生的外泌体中血管紧张素转换酶（ACE）水平升高，外泌体中的ACE转运到VSMCs可促进VSMCs的血管紧张素II（Ang II）生成，通过AT1受体介导，进而促进VSMCs迁移。正常对照大鼠（WKY）VAFs的外泌体中的miR55-5p抑制VSMCs增殖，其效应是通过抑制VSMCs中ACE表达实现的；SHR的VAFs产生的外泌体中的miR155-5p水平降低和ACE水平升高，这是SHR的外泌体促进VSMCs增殖的主要机制。SHR大鼠miR155-5p过表达可减轻高血压，血管平滑肌增殖和血管重构。SHR的尾静脉多次注射WKY的外泌体减轻而SHR的外泌体加重高血压和血管重构。miR155-5p抑制VSMCs表型转换和迁移，其效应是通过抑制ACE表达进而减轻氧化应激和炎症实现的。SHR的VAFs产生的外泌体抑制VSMCs中FNDC5表达，进而促进VSMCs增殖，加重SHR的高血压和血管重构。FNDC5抑制SHR的VSMCs增殖、迁移，其机制与抑制VSMCs的氧化应激和NLRP3炎性小体激活及炎症有关。FNDC5过表达可减轻SHR的高血压和血管重构。本项目发现VAFs的外泌体对VSMCs表型转换、增殖和迁移中起重要调控作用，ACE、miR155-5p和FNDC5是干预高血压的重要分子靶点。

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