Proliferation of vascular smooth muscle cells (VSMCs) plays crucial roles in vascular remodelling and stiffening in hypertension. Vascular adventitial fibroblasts are a key regulator of vascular wall function and structure. This study is designed to investigate the roles of adventitial fibroblasts-derived extracellular vesicles (EVs) in VSMC proliferation and vascular remodelling in normotensive Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR), an animal model of human essential hypertension. EVs were isolated from aortic adventitial fibroblasts of WKY (WKY-EVs) and SHR (SHR-EVs). Compared with WKY-EVs, miR155-5p content was reduced, while angiotensin-converting enzyme (ACE) content was increased in SHR-EVs. WKY-EVs inhibited VSMC proliferation of SHR, which was prevented by miR155-5p inhibitor. SHR-EVs promoted VSMC proliferation of both strains, which was enhanced by miR155-5p inhibitor, but abolished by captopril or losartan. Dual luciferase reporter assay showed that ACE was a target gene of miR155-5p. MiR155-5p mimic or overexpression inhibited VSMC proliferation and ACE upregulation of SHR. WKY-EVs reduced ACE mRNA and protein expressions while SHR-EVs only increased ACE protein level in VSMCs of both strains. However, the SHR-EVs-derived from the ACE knockdown-treated adventitial fibroblasts lost the roles in promoting VSMC proliferation and ACE upregulation. Systemic miR155-5p overexpression reduced vascular ACE, angiotensin II and proliferating cell nuclear antigen levels, and attenuated hypertension and vascular remodelling in SHR. Repetitive intravenous injection of SHR-EVs increased blood pressure and vascular ACE contents, and promoted vascular remodelling in both strains, while WKY-EVs reduced vascular ACE contents and attenuated hypertension and vascular remodelling in SHR. We concluded that WKY-EVs-mediated miR155-5p transfer attenuates VSMC proliferation and vascular remodelling in SHR via suppressing ACE expression, while SHR-EVs-mediated ACE transfer promotes VSMC proliferation and vascular remodelling.

中文翻译：

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外膜成纤维细胞来源的细胞外囊泡中的MiR155-5p通过抑制血管紧张素转化酶的表达来抑制血管平滑肌细胞的增殖。

血管平滑肌细胞（VSMC）的增殖在高血压的血管重塑和硬化中起着至关重要的作用。血管外膜成纤维细胞是血管壁功能和结构的关键调节剂。这项研究旨在调查外源性成纤维细胞衍生的细胞外囊泡（EVs）在正常高血压Wistar-Kyoto大鼠（WKY）和自发性高血压大鼠（SHR）（人类原发性高血压动物模型）中的VSMC增殖和血管重塑中的作用。从WKY（WKY-EV）和SHR（SHR-EV）的主动脉外膜成纤维细胞中分离出EV。与WKY-EV相比，SHR-EV中miR155-5p的含量降低了，而血管紧张素转换酶（ACE）的含量却增加了。WKY-EVs抑制SHR的VSMC增殖，这被miR155-5p抑制剂阻止。SHR-EVs促进了两个菌株的VSMC增殖，miR155-5p抑制剂增强了SHR-EV的增殖，但卡托普利或氯沙坦取消了SHR-EV。双重荧光素酶报告基因测定表明ACE是miR155-5p的靶基因。MiR155-5p的模拟或过度表达抑制了SHR的VSMC增殖和ACE上调。WKY-EVs降低了ACE mRNA和蛋白表达，而SHR-EVs仅提高了两种菌株的VSMC中的ACE蛋白水平。但是，ACE敲除处理的外膜成纤维细胞衍生的SHR-EV失去了促进VSMC增殖和ACE上调的作用。全身性miR155-5p过表达减少了SHR中的血管ACE，血管紧张素II和增殖的细胞核抗原水平，并减轻了高血压和血管重塑。重复静脉注射SHR-EV可增加血压和血管ACE含量，并促进两种菌株的血管重塑，而WKY-EVs降低了SHR中的血管ACE含量并减轻了高血压和血管重塑。我们得出的结论是，WKY-EVs介导的miR155-5p转移通过抑制ACE表达来减弱SHR中的VSMC增殖和血管重塑，而SHR-EVs介导的ACE转移促进VSMC增殖和血管重塑。