MiR155‐5p in adventitial fibroblasts‐derived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing angiotensin‐converting enzyme expression
Tóm tắt
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.
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