Wang Jing-Xiao, Xu Xiao-Yu, Dong Hong-Ke, Wang Yi-Ming, Dai Min, Zhou Bing, Li Yue-Hua, Zhu Guo-Qing, Xiong Xiao-Qing
Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Pathology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China.
J Extracell Vesicles. 2025 Aug;14(8):e70146. doi: 10.1002/jev2.70146.
Vascular adventitial fibroblasts (VAFs) contribute to vascular remodelling in hypertension. However, the mechanisms by which VAFs regulate vascular smooth muscle cells (VSMCs) in vascular remodelling are not well known. Here we report the crucial roles of extracellular nanoparticles exomeres (EMs) derived from VAFs in promoting VSMCs proliferation, migration and vascular remodelling in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). VSMCs' proliferation and migration were enhanced by EMs of SHR via the uptake of EMs in VSMCs, but not by EMs of WKY. Proteomics analysis showed that increased osteopontin (OPN) content may be responsible for the roles of EMs of SHR, which was confirmed by the fact that EMs of SHR pretreated with OPN knockdown lost their roles in promoting VSMCs proliferation and migration. OPN successively promoted the phosphorylation of FAK, PI3K and AKT via acting on integrin αVβ3. Inhibition of integrin αVβ3, FAK, PI3K or AKT almost abolished the effects of EMs of SHR on VSMCs proliferation and migration. Knockdown of OPN in the carotid artery attenuated local vascular remodelling in SHR. Repetitive intravenous injection of EMs of SHR increased blood pressure and promoted vascular remodelling in WKY and SHR. We conclude that EMs from VAFs of SHR promote VSMCs proliferation, migration and vascular remodelling via transferring OPN and subsequently activating integrin αVβ3/FAK/PI3K/AKT signalling pathway.
血管外膜成纤维细胞（VAFs）在高血压血管重塑中发挥作用。然而，VAFs在血管重塑过程中调节血管平滑肌细胞（VSMCs）的机制尚不清楚。在此，我们报告了源自VAFs的细胞外纳米颗粒外泌体（EMs）在正常血压的Wistar-Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）中促进VSMCs增殖、迁移和血管重塑的关键作用。SHR的EMs通过被VSMCs摄取增强了VSMCs的增殖和迁移，但WKY的EMs则无此作用。蛋白质组学分析表明，骨桥蛋白（OPN）含量增加可能是SHR的EMs发挥作用的原因，这一点通过用OPN敲低预处理的SHR的EMs失去其促进VSMCs增殖和迁移的作用得到证实。OPN通过作用于整合素αVβ3依次促进FAK、PI3K和AKT的磷酸化。抑制整合素αVβ3、FAK、PI3K或AKT几乎消除了SHR的EMs对VSMCs增殖和迁移的影响。在SHR的颈动脉中敲低OPN可减轻局部血管重塑。重复静脉注射SHR的EMs可使WKY和SHR的血压升高并促进血管重塑。我们得出结论，SHR的VAFs来源的EMs通过传递OPN并随后激活整合素αVβ3/FAK/PI3K/AKT信号通路促进VSMCs增殖、迁移和血管重塑。
