title: Extracellular vesicles in cardiovascular calcification: expanding current paradigms.
abstract: Vascular calcification is a major contributor to the progression of cardiovascular disease, one of the leading causes of death in industrialized countries. New evidence on the mechanisms of mineralization identified calcification-competent extracellular vesicles (EVs) derived from smooth muscle cells, valvular interstitial cells and macrophages as the mediators of calcification in diseased heart valves and atherosclerotic plaques. However, the regulation of EV release and the mechanisms of interaction between EVs and the extracellular matrix leading to the formation of destabilizing microcalcifications remain unclear. This review focuses on current limits in our understanding of EVs in cardiovascular disease and opens up new perspectives on calcific EV biogenesis, release and functions within and beyond vascular calcification. We propose that, unlike bone-derived matrix vesicles, a large population of EVs implicated in cardiovascular calcification are of exosomal origin. Moreover, the milieu-dependent loading of EVs with microRNA and calcification inhibitors fetuin-A and matrix Gla protein suggests a novel role for EVs in intercellular communication, adding a new mechanism to the pathogenesis of vascular mineralization. Similarly, the cell type-dependent enrichment of annexins 2, 5 or 6 in calcifying EVs posits one of several emerging factors implicated in the regulation of EV release and calcifying potential. This review aims to emphasize the role of EVs as essential mediators of calcification, a major determinant of cardiovascular mortality. Based on recent findings, we pinpoint potential targets for novel therapies to slow down the progression and promote the stability of atherosclerotic plaques.
authors.affiliation: Center for Excellence in Vascular Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Jona B
authors.initials: JB
authors.lastname: Krohn
authors.affiliation: Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Boston, MA, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Hutcheson
authors.affiliation: Center for Excellence in Vascular Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: Center for Excellence in Vascular Biology, Harvard Medical School, Boston, MA, USA.|Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School, Boston, MA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D061205:Vascular Calcification / Q000378:metabolism* / Q000473:pathology
chemical_list: D035683:MicroRNAs
references.citation: Eur J Clin Invest. 2015 Sep;45(9):976-85
references.pmid: 26153098
references.citation: Circ Res. 2011 Sep 2;109(6):697-711
references.pmid: 21885837
references.citation: J Bone Miner Res. 2010 Jan;25(1):141-53
references.pmid: 19580468
references.citation: PLoS One. 2013 May 22;8(5):e64558
references.pmid: 23717629
references.citation: JAMA. 2014 Jan 15;311(3):271-8
references.pmid: 24247483
references.citation: J Biol Chem. 2012 Mar 2;287(10):7503-11
references.pmid: 22253433
references.citation: J Am Soc Nephrol. 2004 Nov;15(11):2857-67
references.pmid: 15504939
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Bone. 2015 Oct;79:29-36
references.pmid: 25980744
references.citation: J Cell Biol. 1997 Jun 2;137(5):1149-60
references.pmid: 9166414
references.citation: Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):724-36
references.pmid: 24558104
references.citation: Nat Med. 2014 Apr;20(4):368-76
references.pmid: 24584117
references.citation: J Cell Physiol. 2007 Feb;210(2):325-35
references.pmid: 17096383
references.citation: Nat Mater. 2016 Mar;15(3):335-43
references.pmid: 26752654
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5003-8
references.pmid: 21383194
references.citation: J Cell Sci. 2004 Jan 26;117(Pt 3):441-9
references.pmid: 14679310
references.citation: Circ Res. 2011 Jun 24;109(1):e1-12
references.pmid: 21566214
references.citation: Curr Opin Lipidol. 2014 Oct;25(5):327-32
references.pmid: 25188916
references.citation: Nat Cell Biol. 2012 Feb 12;14(3):249-56
references.pmid: 22327366
references.citation: PLoS One. 2015 Jun 26;10(6):e0131589
references.pmid: 26115487
references.citation: Cardiovasc Pathol. 2004 Jan-Feb;13(1):3-10
references.pmid: 14761779
references.citation: Circ Res. 2015 Apr 10;116(8):1312-23
references.pmid: 25711438
references.citation: Kidney Int. 2010 Mar;77(5):436-42
references.pmid: 20016465
references.citation: Ann Biomed Eng. 2006 Oct;34(10):1535-41
references.pmid: 17006755
references.citation: J Am Coll Cardiol. 2012 Apr 24;59(17):1539-48
references.pmid: 22516444
references.citation: Nat Rev Mol Cell Biol. 2005 Jun;6(6):449-61
references.pmid: 15928709
references.citation: Am J Pathol. 2011 Oct;179(4):1594-600
references.pmid: 21806957
references.citation: Circ Res. 2013 Jun 21;113(1):72-7
references.pmid: 23616621
references.citation: Sci Signal. 2009 Dec 08;2(100):ra81
references.pmid: 19996457
references.citation: Biochem Biophys Res Commun. 2008 Apr 4;368(2):267-72
references.pmid: 18230348
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: J Am Coll Cardiol. 2007 Feb 20;49(7):772-7
references.pmid: 17306706
references.citation: PLoS One. 2014 Sep 15;9(9):e107482
references.pmid: 25222280
references.citation: Curr Opin Cell Biol. 2015 Aug;35:69-77
references.pmid: 26001269
references.citation: Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25
references.pmid: 19603039
references.citation: J Am Coll Cardiol. 2007 May 8;49(18):1860-70
references.pmid: 17481445
references.citation: J Clin Invest. 2011 Jul;121(7):2921-31
references.pmid: 21646721
references.citation: J Bone Miner Res. 1995 Nov;10(11):1614-24
references.pmid: 8592937
references.citation: J Bone Miner Res. 2008 Nov;23(11):1798-805
references.pmid: 18597635
references.citation: Circ Cardiovasc Genet. 2009 Aug;2(4):379-88
references.pmid: 20031610
references.citation: J Biol Chem. 2000 Nov 10;275(45):35577-83
references.pmid: 10956650
references.citation: Exp Cell Res. 2009 May 15;315(9):1584-92
references.pmid: 18930046
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10741-6
references.pmid: 23733926
references.citation: Biochim Biophys Acta. 2009 Dec;1790(12):1592-8
references.pmid: 19786074
references.citation: Cardiovasc Res. 2012 Mar 15;93(4):633-44
references.pmid: 22258631
references.citation: Circulation. 2007 Dec 11;116(24):2841-50
references.pmid: 18040026
references.citation: Fed Proc. 1976 Feb;35(2):156-62
references.pmid: 1248649
references.citation: J Biol Chem. 2007 Sep 7;282(36):26035-45
references.pmid: 17613532
references.citation: Physiol Rev. 2002 Apr;82(2):331-71
references.pmid: 11917092