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

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.

SUBMITTER: Ren XS

PROVIDER: S-EPMC6896498 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Ren Xing-Sheng XS Tong Ying Y Qiu Yun Y Ye Chao C Wu Nan N Xiong Xiao-Qing XQ Wang Jue-Jin JJ Han Ying Y Zhou Ye-Bo YB Zhang Feng F Sun Hai-Jian HJ Gao Xing-Ya XY Chen Qi Q Li Yue-Hua YH Kang Yu-Ming YM Zhu Guo-Qing GQ

Journal of extracellular vesicles 20191202 1

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 h ...[more]

PMID: 31839907

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Project description:Angiotensin converting enzyme (ACE) is known for converting inactive angiotensin I into the potent vasoconstrictor angiotensin II, playing a critical role in blood pressure regulation. However, there is evidence that the dicarboxypeptidase activity of ACE is also essential for other physiological processes likely through processing of various peptide substrates. This study used mass spectrometry for the comprehensive detection and identification of natural substrates and products of ACE within the mouse plasma peptidome. The plasma peptidome of ACE KO mice was obtained through a multi-step purification process which included organic TCA precipitation as well as size exclusion and reversed phase chromatography. The obtained complex mixture of endogenous peptides was then subjected to in vitro cleavage by ACE. ACE-treated and untreated samples were then analyzed by LC/MS on an Orbitrap mass spectrometer, followed by alignment of MS1 data by Progenesis QI software. The MS1 signals that gained or lost intensity after treatment with ACE, were considered as possible products and substrates of ACE, respectively, and were selected for a targeted MS/MS analysis, and subsequently identified with PEAKS 8.5 and Proteome Discoverer software. Results. Close to 250 natural peptides were identified as possible substrates and products of ACE, demonstrating the high promiscuity of the enzyme. The use of internal standards as well as detection of some expected endogenous peptides, such as angiotensin II and bradykinin, supported the validity of the approach. Some of the newly identified substrates of ACE are known for their biological activities. For example, a fragment of complement C3, the 17-amino acid peptide C3f, exhibits spasminogenic activity and was processed by ACE. ACE cleavage of select peptides was further confirmed in vitro. Also, concentrations of ACE substrates in plasma from mice with variant genetic ACE domain backgrounds were determined by LC/MS using multiple reaction monitoring on a triple quadrupole mass spectrometer. The in vivo results were consistent with the in vitro results, in the sense that higher levels of the ACE substrates were observed when the respective processing domain was knocked out. The use of transgenic mice as well as ACE with single active domain allowed clarifying the ACE domain selectivity towards individual peptide substrates. This study resulted in creation of a library of substrates and products of ACE that can be further tested for their biological function and can help to elucidate the link between ACE and the numerous physiological effects attributed to its activity.

Dataset Information

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

Publications

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

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