Endothelial cell-derived extracellular vesicles in atherosclerosis: the emerging value for diagnosis, risk stratification and prognostication

Abstract

Endothelial cell-derived extracellular vesicles are produced by both activated and apoptotic endothelial cells, and play a pivotal role in various physiological conditions such as inflammation, repair, programmed cell death, and immune responses. There is a large body of evidence on the dysregulation of synthesis and secretion of several types of endothelial cell-derived extracellular vesicles, which can then trigger microvascular inflammation, atherosclerotic plaque formation, plaque rupture, thrombosis and endothelial dysfunction. The development of atherosclerosis and cardiovascular events is associated with an increased number of apoptotic, endothelial cell-derived vesicles and a decrease in activated, endothelial cell-derived vesicles. This review depicts the role of endothelial cell-derived extracellular vesicles in the manifestation and progression of atherosclerosis. We also discuss the clinical use and benefits of altering the immune phenotypes of extracellular vesicles originating from endothelial cells, to function as predictive biomarkers in both asymptomatic and subclinical atherosclerosis.

Keywords

Atherosclerosis / cardiovascular events / extracellular vesicles / endothelial cells

References

[1] Herrington W,Sherliker P,Lewington S.Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease..Circ Res2016;118:535-46

[2] Barquera S,Medina C,Bibbins-Domingo K.Global overview of the epidemiology of atherosclerotic cardiovascular disease..Arch Med Res2015;46:328-38

[3] Moran AE,Forouzanfar MH,Mensah GA.Variations in ischemic heart disease burden by age, country, and income: the Global Burden of Diseases, Injuries, and Risk Factors 2010 study..Glob Heart2014;9:91-9 PMCID:PMC4071302

[4] Cairns BJ,Canoy D,Reeves GK.Variations in vascular mortality trends, 2001-2010, among 1.3 million women with different lifestyle risk factors for the disease..Eur J Prev Cardiol2015;22:1626-34 PMCID:PMC4639812

[5] Li K,Kaaks R.Lifestyle risk factors and residual life expectancy at age 40: a German cohort study..BMC Med2014;12:59 PMCID:PMC4022368

[6] Gimbrone MA Jr.Endothelial cell dysfunction and the pathobiology of atherosclerosis..Circ Res2016;118:620-36 PMCID:PMC4762052

[7] Horio E,Miyata K,Hosokawa K.Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression..Arterioscler Thromb Vasc Biol2014;34:790-800

[8] Stoll G.Inflammation and atherosclerosis: novel insights into plaque formation and destabilization..Stroke2006;37:1923-32

[9] Libby P,Tall AR.Atherosclerosis: successes, surprises, and future challenges..Circ Res2016;118:531-4 PMCID:PMC4762065

[10] Rader DJ.Human genetics of atherothrombotic disease and its risk factors..Arterioscler Thromb Vasc Biol2015;35:741-7

[11] Dron JS,Hegele RA.Recent advances in the genetics of atherothrombotic disease and its determinants..Arterioscler Thromb Vasc Biol2017;37:e158-66

[12] Boulanger CM,Rautou PE.Extracellular vesicles in coronary artery disease..Nat Rev Cardiol2017;14:259-72

[13] Nguyen MA,Geoffrion M,Tandoc K.Extracellular vesicles secreted by atherogenic macrophages transfer microRNA to inhibit cell migration..Arterioscler Thromb Vasc Biol2018;38:49-63 PMCID:PMC5884694

[14] Deng W,Hou Y,Wang Y.Extracellular vesicles in atherosclerosis..Clin Chim Acta2019;495:109-17

[15] Hafiane A.Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease..Metabolism2018;85:213-22

[16] Boilard E.Extracellular vesicles and their content in bioactive lipid mediators: more than a sack of microRNA..J Lipid Res2018;59:2037-46 PMCID:PMC6210911

[17] Théry C,Aikawa E,Anderson JD.Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines..J Extracell Vesicles2018;7:1535750 PMCID:PMC6322352

[18] Clayton A,Buzas EI,Falcón-Perez JM.Considerations towards a roadmap for collection, handling and storage of blood extracellular vesicles..J Extracell Vesicles2019;8:1647027 PMCID:PMC6711123

[19] Hill AF,Lambertz U,O’Driscoll L.ISEV position paper: extracellular vesicle RNA analysis and bioinformatics..J Extracell Vesicles2014;2:22859 PMCID:PMC3873759

[20] Raimondo F,Chinello C,Pitto M.Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery..Proteomics2011;11:709-20

[21] Corrado C,Chiesi A,De Leo G.Exosomes as intercellular signaling organelles involved in health and disease: basic science and clinical applications..Int J Mol Sci2013;14:5338-66 PMCID:PMC3634447

[22] Tual-Chalot S,Andriantsitohaina R.Microvesicles: intercellular vectors of biological messages..Mol Interv2011;11:88-94

[23] Soo CY,Zheng Y,Riches AC.Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells..Immunology2012;136:192-7 PMCID:PMC3403268

[24] Huang XY,Tschannen M,Jacob H.Characterization of human plasma-derived exosomal rnas by deep sequencing..BMC Genomics2013;14:14 PMCID:PMC3653748

[25] de Jong OG,Chen Y,Gremmels H.Cellular stress conditions are reflected in the protein and rna content of endothelial cell-derived exosomes..J Extracell Vesicles2012;1: PMCID:PMC3760650

[26] Waldenstrom A,Hellman U.Cardiomyocyte microvesicles contain dna/rna and convey biological messages to target cells..PLoS One2012;7:7 PMCID:PMC3323564

[27] Camussi G,Bruno S,Fonsato V.Exosome/microvesicle-mediated epigenetic reprogramming of cells..Am J Cancer Res2011;1:98-110 PMCID:PMC3180104

[28] Caruso S.Apoptotic cell-derived extracellular vesicles: more than just debris..Front Immunol2018;9:1486 PMCID:PMC6031707

[29] Boon RA.Intercellular transport of micrornas..Arterioscler Thromb Vasc Biol2013;33:186-92 PMCID:PMC3580056

[30] Gump JM.Autophagy and apoptosis: what is the connection?.Trends Cell Biol2011;21:387-92 PMCID:PMC3539742

[31] Jiang L,Caruso S,Phan TK.Determining the contents and cell origins of apoptotic bodies by flow cytometry..Sci Rep2017;7:14444 PMCID:PMC5663759

[32] Akers JC,Kim R,Chen CC.Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies..J Neurooncol2013;113:1-11 PMCID:PMC5533094

[33] Orlando KA,Pittman RN.Rho kinase regulates fragmentation and phagocytosis of apoptotic cells..Exp Cell Res2006;312:5-15

[34] Tasdemir E,Maiuri MC,Vitale I.Methods for assessing autophagy and autophagic cell death..Methods Mol Biol2008;445:29-76

[35] Simpson RJ,Moritz RL.Exosomes: proteomic insights and diagnostic potential..Expert Rev Proteomics2009;6:267-83

[36] Mause SF.Microparticles: protagonists of a novel communication network for intercellular information exchange..Circ Res2010;107:1047-57

[37] El Andaloussi S,Breakefield XO.Extracellular vesicles: Biology and emerging therapeutic opportunities..Nat Rev Drug Discov2013;12:348-58

[38] Yu X,Wang D,Chen X.Mechanism of TNF-alpha autocrine effects in hypoxic cardiomyocytes: Initiated by hypoxia inducible factor 1 alpha, presented by exosomes..J Mol Cell Cardiol2012;53:848-57

[39] Tian J,Liu XM,Weng QF.Extracellular hsp60 induces inflammation through activating and up-regulating TLRs in cardiomyocytes..Cardiovasc Res2013;98:391-401

[40] Hoyer FF,Werner N.Microparticles - messengers of biological information..J Cell Mol Med2010;14:2250-6 PMCID:PMC3822564

[41] Todorova D,Lacroix R,Dignat-George F.Extracellular vesicles in angiogenesis..Circ Res2017;120:1658-73 PMCID:PMC5426696

[42] Bagi Z,Broskova Z,Yeo T.Extracellular vesicle integrins act as a nexus for platelet adhesion in cerebral microvessels..Sci Rep2019;9:15847 PMCID:PMC6825169

[43] Figliolini F,Grange C,Tapparo M.Extracellular vesicles from adipose stem cells prevent muscle damage and inflammation in a mouse model of hind limb ischemia: role of neuregulin-1..Arterioscler Thromb Vasc Biol2020;40:239-54

[44] Chatterjee V,Ma Y,Meegan JE.Endothelial microvesicles carrying Src-rich cargo impair adherens junction integrity and cytoskeleton homeostasis..Cardiovasc Res2019;cvz238

[45] Berezin A.Neutrophil extracellular traps: The core player in vascular complications of diabetes mellitus..Diabetes Metab Syndr2019;13:3017-23

[46] Dalli J,Norling LV,Hinds C.Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties..Mol Cell Proteomics2013;12:2205-19 PMCID:PMC3734580

[47] Banfi C,Wait R,Gianazza E.Proteome of endothelial cell-derived procoagulant microparticles..Proteomics2005;5:4443-55

[48] Camus SM,Bonnin P,Le Jeune S.Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vaso occlusions in sickle cell disease..Blood2015;125:3805-14 PMCID:PMC4490297

[49] Chang YJ,Wu CC,Huang TC.Extracellular microRNA-92a mediates endothelial cell-macrophage communication..Arterioscler Thromb Vasc Biol2019;39:2492-504 PMCID:PMC6879873

[50] Loyer X,Vion AC,Boulkroun S.Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice..Circ Res2014;114:434-43

[51] Liu Y,Hosen MR,Flender A.Atherosclerotic conditions promote the packaging of functional microRNA-92a-3p into endothelial microvesicles..Circ Res2019;124:575-87

[52] Fang Y.Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium..Arterioscler Thromb Vasc Biol2012;32:979-87 PMCID:PMC3306477

[53] He S,Xiao J,Sun Z.Endothelial extracellular vesicles modulate the macrophage phenotype: Potential implications in atherosclerosis..Scand J Immunol2018;87:e12648

[54] Wu W,Laguna-Fernandez A,Wang KC.Flow-dependent regulation of kruppel-like factor 2 is mediated by microRNA-92a..Circulation2011;124:633-41 PMCID:PMC3511909

[55] Gou L,Song W,Liu J.Inhibition of miR-92a Suppresses oxidative stress and improves endothelial function by upregulating heme oxygenase-1 in db/db Mice..Antioxid Redox Signal2018;28:358-70

[56] Yang J,Lü S,Ma X.T-cell-derived extracellular vesicles regulate B-cell IgG production via pyruvate kinase muscle isozyme 2..FASEB J2019;33:12780-99 PMCID:PMC6902684

[57] Žėkas V,Karčiauskaitė D,Burokienė N.Chronic and oxidative stress association with total count of endothelial microvesicles in healthy young male plasma..Adv Clin Exp Med2019;28:683-92

[58] Berezin AE,Samura TA.Altered signature of apoptotic endothelial cell-derived microvesicles predicts chronic heart failure phenotypes..Biomark Med2019;13:737-50

[59] Wang Z,Zhang S,Wang Z.MiR-30e and miR-92a are related to atherosclerosis by targeting ABCA1..Mol Med Rep2019;19:3298-304

[60] Iaconetti C,Sorrentino S,Pironti G.Inhibition of miR-92a increases endothelial proliferation and migration in vitro as well as reduces neointimal proliferation in vivo after vascular injury..Basic Res Cardiol2012;107:296

[61] Kang S,Jeong JY,An HJ.Size distribution of serum extracellular vesicles in mice with atherosclerosis..Pathol Res Pract2019;215:152574

[62] Yang W,Hou Y,Chen T.Extracellular vesicles in vascular calcification..Clin Chim Acta2019;499:118-22

[63] Chimen M,Box CL,Hazeldine J.Appropriation of GPIbα from platelet-derived extracellular vesicles supports monocyte recruitment in systemic inflammation..Haematologica2019;haematol.2018.215145 PMCID:PMC7193470

[64] Wang Y,Zhang A,Fang Z.Exosomes: an emerging factor in atherosclerosis..Biomed Pharmacother2019;115:108951

[65] Wadey RM,Mathew D,Rees DA.Inflammatory adipocyte-derived extracellular vesicles promote leukocyte attachment to vascular endothelial cells..Atherosclerosis2019;283:19-27

[66] Blaser MC.Differential miRNA loading underpins dual harmful and protective roles for extracellular vesicles in atherogenesis..Circ Res2019;124:467-9 PMCID:PMC6383776

[67] Wang J,Li C,Li S.MicroRNA-92a promotes vascular smooth muscle cell proliferation and migration through the ROCK/MLCK signalling pathway..J Cell Mol Med2019;23:3696-710 PMCID:PMC6484312

[68] Zhou J,Nguyen P,Weiss A.Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress..Circ Res2013;113:40-51 PMCID:PMC3772783

[69] Liu H,Zhao W.Inhibition of miR-92a may protect endothelial cells after acute myocardial infarction in rats: role of KLF2/4..Med Sci Monit2016;22:2451-62 PMCID:PMC4957625

[70] Zhang YY,Zhu N,Deng CF.Autophagy: a killer or guardian of vascular smooth muscle cells..J Drug Target2020;1-7

[71] Rogg EM,Bischof C,Schulz MH.Analysis of cell type-specific effects of microRNA-92a provides novel insights into target regulation and mechanism of action..Circulation2018;138:2545-58

[72] Daniel JM,Teske R,Koch A.Inhibition of miR-92a improves re-endothelialization and prevents neointima formation following vascular injury..Cardiovasc Res2014;103:564-72 PMCID:PMC4145012

[73] Yamada NO,Akao Y.Extracellular vesicles containing microRNA-92a-3p facilitate partial endothelial-mesenchymal transition and angiogenesis in endothelial cells..Int J Mol Sci2019;20:E4406 PMCID:PMC6769671

[74] Barbati C,Colasanti T,Marcosano M.Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rheumatoid arthritis..Immunol Res2018;66:655-62

[75] Kapustin AN,Drozdov I,Davidson SM.Vascular smooth muscle cell calcification is mediated by regulated exosome secretion..Circ Res2015;116:1312-23

[76] Goettsch C,Aikawa M,Pham T.Sortilin mediates vascular calcification via its recruitment into extracellular vesicles..J Clin Invest2016;126:1323-36 PMCID:PMC4811143

[77] Chiva-Blanch G,Alonso R,Perez de Isla L.Liquid biopsy of extracellular microvesicles maps coronary calcification and atherosclerotic plaque in asymptomatic patients with familial hypercholesterolemia..Arterioscler Thromb Vasc Biol2019;39:945-55

[78] Creager MD,Hutcheson JD,Schlotter F.¹⁸F-fluoride signal amplification identifies microcalcifications associated with atherosclerotic plaque instability in positron emission tomography/computed tomography images..Circ Cardiovasc Imaging2019;12:e007835 PMCID:PMC6338081

[79] Adamson PD,Joshi NV,Dweck MR.Salt in the wound: (18)F-fluoride positron emission tomography for identification of vulnerable coronary plaques..Cardiovasc Diagn Ther2015;5:150-5 PMCID:PMC4420673

[80] Dweck MR,Joshi NV,Jones C.Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology..J Am Coll Cardiol2012;59:1539-48

[81] New SE,Aikawa M,Shibasaki M.Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques..Circ Res2013;113:72-7 PMCID:PMC3703850

[82] Sodek J,Huynh MH,Ringuette M.Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC..Connect Tissue Res2002;43:308-19

[83] Martins M,Martins A,Neves NM.Extracellular vesicles derived from osteogenically induced human bone marrow mesenchymal stem cells can modulate lineage commitment..Stem Cell Reports2016;6:284-91 PMCID:PMC4788762

[84] Krohn JB,Martínez-Martínez E,Bouten CV.Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-β signaling..Arterioscler Thromb Vasc Biol2016;36:525-33 PMCID:PMC4767541

[85] Alique M,Bodega G,Ramírez R.Senescent Microvesicles: a novel advance in molecular mechanisms of atherosclerotic calcification..Int J Mol Sci2018;19:E2003 PMCID:PMC6073566

[86] Blaser MC.Roles and regulation of extracellular vesicles in cardiovascular mineral metabolism..Front Cardiovasc Med2018;5:187 PMCID:PMC6308298

[87] Paone S,Hulett MD.Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis..Cell Mol Life Sci2019;76:1093-106

[88] Wei Y,Neth P,Schober A.MicroRNA-126, -145, and -155: a therapeutic triad in atherosclerosis?.Arterioscler Thromb Vasc Biol2013;33:449-54

[89] Zhao Y,Luo P,Yang J.XBP1 splicing triggers miR-150 transfer from smooth muscle cells to endothelial cells via extracellular vesicles..Sci Rep2016;6:28627 PMCID:PMC4919660

[90] Yin M,Boulanger CM.Extracellular vesicles as new pharmacological targets to treat atherosclerosis..Eur J Pharmacol2015;763:90-103

[91] Togliatto G,Rosso A,Gili M.PDGF-BB carried by endothelial cell-derived extracellular vesicles reduces vascular smooth muscle cell apoptosis in diabetes..Diabetes2018;67:704-16

[92] Sanden M,Nielsen MRS,Schmidt EB.BLTR1 and CD36 expressing microvesicles in atherosclerotic patients and healthy individuals..Front Cardiovasc Med2018;5:156 PMCID:PMC6218418

[93] Pretorius L,Adams RCM,Laubscher WA.Platelet activity and hypercoagulation in type 2 diabetes..Cardiovasc Diabetol2018;17:141 PMCID:PMC6214175

[94] Vítková V,Janota J.Endothelial cell-derived microvesicles: potential mediators and biomarkers of pathologic processes..Biomark Med2018;12:161-75

[95] Shi C,Deng J,O’Brien ER.Characterization of heat shock protein 27 in extracellular vesicles: a potential anti-inflammatory therapy..FASEB J2019;33:1617-30

[96] Jansen F,Pfeifer A.Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease..JACC Basic Transl Sci2017;2:790-807 PMCID:PMC6059011

[97] Hutcheson JD.Extracellular vesicles in cardiovascular homeostasis and disease..Curr Opin Cardiol2018;33:290-7 PMCID:PMC5895489

[98] Jansen F,Werner N.Extracellular vesicles in cardiovascular disease: potential applications in diagnosis, prognosis, and epidemiology..Circ Res2017;120:1649-57

[99] Pardo F,Sobrevia B,Sobrevia L.Extracellular vesicles in obesity and diabetes mellitus..Mol Aspects Med2018;60:81-91

[100] Li F,Rao L,Zhao X.Research progress on exosomes in diagnosis and treatment of cardiovascular diseases..Zhejiang Da Xue Xue Bao Yi Xue Ban2018;47:320-6(in Chinese)

[101] Dickhout A.Extracellular vesicles as biomarkers in cardiovascular disease; chances and risks..Front Cardiovasc Med2018;5:113 PMCID:PMC6113364

[102] Berezin AE,Berezina T.The signature of circulating microparticles in heart failure patients with metabolic syndrome..J Circ Biomark2016;5:1849454416663659 PMCID:PMC5548327

[103] Berezin AE,Martovitskaya YV,Berezina TA.The predictive role of circulating microparticles in patients with chronic heart failure..BBA Clin2014;3:18-24 PMCID:PMC4661507

[104] Berezin AE,Berezina TA.The pattern of circulating microparticles in patients with diabetes mellitus with asymptomatic atherosclerosis..Acta Clin Belg2016;71:38-45

[105] Bei Y,Banciu DD,Xiao J.Circulating exosomes in cardiovascular diseases..Adv Exp Med Biol2017;998:255-69

[106] Zamani P,Butler AE,Sahebkar A.The therapeutic and diagnostic role of exosomes in cardiovascular diseases..Trends Cardiovasc Med2019;29:313-23

[107] Lu M,Li S,Liu M.The exosome-derived biomarker in atherosclerosis and its clinical application..J Cardiovasc Transl Res2019;12:68-74