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

Journal of extracellular vesicles - Tập 9 Số 1 - 2020
Xingsheng Ren1,2, Ying Tong1,2, Yun Qiu1, Chao Ye1, Nan Wu1, Xiao‐Qing Xiong1, Juejin Wang1, Ying Han1, Ye‐Bo Zhou1, Feng Zhang1, Hai‐Jian Sun1, Xing‐Ya Gao1, Qi Chen3, Yuehua Li3, Yu‐Ming Kang4, Guo‐Qing Zhu3,1
1Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China
2These authors equally contributed to this work.
3Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China
4Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine, Xi’an, China

Tóm tắt

ABSTRACTProliferation 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.

Từ khóa


Tài liệu tham khảo

10.1007/s11906-006-0046-3

Ponticos M, 2014, Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis, J Biomed Res., 28, 25, 10.7555/JBR.27.20130064

10.1016/j.bbadis.2014.07.008

10.1146/annurev-physiol-030212-183802

10.1161/HYPERTENSIONAHA.115.06262

Stenmark KR, 2011, The adventitia: essential role in pulmonary vascular remodeling, Compr Physiol, 1, 141

10.1097/HJH.0000000000001654

10.1161/HYPERTENSIONAHA.118.11375

Javeed N, 2017, Exosomes and their role in the micro‐/macro‐environment: a comprehensive review, J Biomed Res., 31, 386, 10.7555/JBR.30.20150162

10.1080/20013078.2018.1548234

10.1080/20013078.2018.1438720

10.1161/ATVBAHA.117.309795

10.1080/20013078.2018.1481321

10.1080/20013078.2017.1400370

10.1016/j.cell.2016.01.043

10.1016/j.coph.2016.06.003

Sun HJ, 2017, Functional roles of exosomes in cardiovascular disorders: a systematic review, Eur Rev Med Pharmacol Sci., 21, 5197

10.1161/CIRCULATIONAHA.116.022478

10.1093/nar/gkh023

10.3892/mmr.2014.2994

10.1002/jcb.25234

10.1016/S1054-8807(03)00135-2

Graham D, 2005, Congenic/consomic models of hypertension, Methods Mol Med, 108, 3

10.1089/ars.2015.6475

Yuen CY, 2012, From skeleton to cytoskeleton: osteocalcin transforms vascular fibroblasts to myofibroblasts via angiotensin II and Toll‐like receptor 4, Circ Res., 111, e55

10.1080/20013078.2018.1535750

Van DJ, 2017, Is your article EV‐TRACKed?, J Extracell Vesicles., 6, 1379835, 10.1080/20013078.2017.1379835

Busato A, 2016, Magnetic resonance imaging of ultrasmall superparamagnetic iron oxide‐labeled exosomes from stem cells: a new method to obtain labeled exosomes, Int J Nanomedicine., 11, 2481

10.1089/scd.2016.0093

10.1016/j.yexcr.2015.12.009

10.1007/s11626-018-0261-7

10.1039/C8SC04197K

10.1002/glia.23299

10.1038/cddis.2016.181

Gallet R, 2017, Exosomes secreted by cardiosphere‐derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction, Eur Heart J, 38, 201

10.18632/oncotarget.21635

10.1186/s12943-017-0740-6

10.1038/cddis.2017.470

10.1016/j.ab.2011.01.037

Zang YH, 2019, FNDC5 inhibits foam cell formation and monocyte adhesion in vascular smooth muscle cells via suppressing NFkappaB‐mediated NLRP3 upregulation, Vascul Pharmacol., 106579, 10.1016/j.vph.2019.106579

10.1038/gt.2011.145

LL Z, 2014, Salusin‐beta in rostral ventrolateral medulla increases sympathetic outflow and blood pressure via superoxide anions in hypertensive rats, J Hypertens., 32, 1059, 10.1097/HJH.0000000000000143

Xu CC, 2008, Differential expression of microRNAs in the aorta of spontaneously hypertensive rats, Sheng Li Xue Bao, 60, 553

Zheng L, 2010, MicroRNA‐155 regulates angiotensin II type 1 receptor expression and phenotypic differentiation in vascular adventitial fibroblasts, Biochem Biophys Res Commun., 400, 483, 10.1016/j.bbrc.2010.08.067

10.1016/j.vph.2015.08.007

10.1056/NEJM200001203420301

10.1161/CIRCULATIONAHA.116.025950

Uehara Y, 1993, Inhibition of protein synthesis and antiproliferative effect of the angiotensin converting enzyme inhibitor trandolaprilat in rat vascular smooth muscle cells, J Hypertens., 11, 1073, 10.1097/00004872-199310000-00011

10.1093/eurheartj/ehs075

10.1136/bmj.k4209

Thông tin
Thông tin xuất bản

Journal of extracellular vesicles

Tập 9 Số 1

Thông tin tác giả