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

Abstract

2020) MiR155-5p in adventitial fibroblastsderived extracellular vesicles inhibits vascular smooth muscle cell proliferation via suppressing ABSTRACT 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. ARTICLE HISTORY

MiR155-5p Inhibits Cell Migration and Oxidative Stress in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats

“…MiR155-5p mimic inhibited ACE mRNA and protein expression in VSMCs of both WKY rats and SHR ( Figure 3A), confirming our previous findings that ACE is one of the targets of miR155-5p, and miR155-5p negatively regulates ACE expression in VSMCs in rat [17]. The miR155-5p inhibitor increased ACE expressions in VSMCs of both WKY rats and SHR ( Figure 3B), suggesting endogenous miR155-5p has a role in inhibiting ACE expression in WKY rats and SHR.…”

“…VSMC migration contributes to maladaptive vascular remodeling in hypertension and is associated with the pathogenesis of hypertension and related organ damage [34][35][36]. Our previous study showed that extracellular vesicles derived from aortic adventitial fibroblasts of normal rats inhibited VSMC proliferation by delivering miR155-5p to VSMCs [17]. The primary new findings of the present study are that miR155-5p inhibits the migration of VSMC from SHR by suppressing ACE expression and its downstream production of superoxide anion and inflammatory factors in VSMCs of SHR.…”

“…We found that miR155-5p attenuated migration, oxidative stress, and inflammation in VSMCs of SHR. Furthermore, we recently showed that miR155-5p attenuated VSMC proliferation and vascular remodeling in SHR [17]. These findings suggest that miR155-5p might be a potential prospect used for inhibiting ACE expression and thereby for attenuating vascular remodeling in hypertension, which needs further investigation.…”

“…It is known that ACE converts Ang I into Ang II, which is critical in promoting VSMC migration via AT1 receptors [35], and is involved in vascular remodeling in hypertension [37][38][39]. The level of miR155-5p was reduced in VSMCs of SHR, and ACE was one of the targets of miR155-5p [17]. We found that the miR155-5p mimic inhibited the migration of VSMC from SHR, which was accompanied by the reduction of ACE mRNA and protein expression, while the miR155-5p inhibitor promoted the migration of VSMC of both WKY rats and SHR, which was accompanied by the upregulation of ACE mRNA and protein expression.…”

“…Recent studies in our lab have shown that miR155-5p level was reduced and angiotensin-converting enzyme (ACE) expression was increased in the aortic media of spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. Extracellular vesicles derived from vascular adventitial fibroblasts of WKY inhibited the proliferation of VSMC of SHR by delivering miR155-5p to VSMCs [17]. Vascular adventitial fibroblast-derived extracellular vesicles in SHR promoted VSMC migration by conveying ACE to VSMCs [18].…”