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  • Review Article
  • Published:

Extracellular vesicles in coronary artery disease

Nature Reviews Cardiology volume 14, pages 259–272 (2017)Cite this article

Subjects

Key Points

  • Extracellular vesicles are released in biological fluids both under basal conditions and in pathological settings

  • Extracellular vesicles act as vectors of biological information by transferring their protein, lipid, and nucleic acid content to target cells

  • Circulating levels of extracellular vesicles of different cellular origin are increased in cardiovascular diseases, including myocardial infarction; these extracellular vesicles could serve as diagnostic and prognostic biomarkers

  • Extracellular vesicles might contribute to atherosclerosis development and progression by promoting initial lesion formation, intravascular calcifications, unstable plaque progression, and thrombus formation after rupture

  • Extracellular vesicles released by stem cells (progenitor or mesenchymal stem cells) have potential therapeutic benefits on cardiac function after myocardial infarction

Abstract

Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.

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Figure 1: Effects of extracellular vesicles on the development of atherosclerosis.
Figure 2: Role of in vivo-generated extracellular vesicles in the development of atherosclerosis.

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References

  1. Wolf, P. The nature and significance of platelet products in human plasma. Br. J. Haematol. 13, 269–288 (1967).

    CAS  PubMed  Google Scholar 

  2. van der Pol, E., Boing, A. N., Gool, E. L. & Nieuwland, R. Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J. Thromb. Haemost. 14, 48–56 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Yanez-Mo, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell.Vesicles 4, 27066 (2015).

    Article  PubMed  Google Scholar 

  4. Morel, O., Jesel, L., Freyssinet, J. M. & Toti, F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler. Thromb. Vasc. Biol. 31, 15–26 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Sapet, C. et al. Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2. Blood 108, 1868–1876 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Vion, A. C. et al. Shear stress regulates endothelial microparticle release. Circ. Res. 112, 1323–1333 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Shet, A. S. et al. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood 102, 2678–2683 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Connor, D. E., Exner, T., Ma, D. D. & Joseph, J. E. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb. Haemost. 103, 1044–1052 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Arraud, N. et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J. Thromb. Haemost. 12, 614–627 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Osteikoetxea, X. et al. Improved characterization of EV preparations based on protein to lipid ratio and lipid properties. PLoS ONE 10, e0121184 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kowal, J. et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl Acad. Sci. USA 113, E968–E977 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Varga, Z. et al. Towards traceable size determination of extracellular vesicles. J. Extracell. Vesicles 3, 23298 (2014).

    Article  CAS  Google Scholar 

  13. Witwer, K. W. et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2, 20360 (2013).

    Article  CAS  Google Scholar 

  14. Boing, A. N. et al. Single-step isolation of extracellular vesicles by size-exclusion chromatography. J. Extracell. Vesicles 3, 23430 (2014).

    Article  Google Scholar 

  15. Lacroix, R. et al. Impact of pre-analytical parameters on the measurement of circulating microparticles: towards standardization of protocol. J. Thromb. Haemost. 10, 437–446 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. van der Pol, E., Coumans, F., Varga, Z., Krumrey, M. & Nieuwland, R. Innovation in detection of microparticles and exosomes. J. Thromb. Haemost. 11 (Suppl. 1), 36–45 (2013).

    Article  PubMed  Google Scholar 

  17. Mulcahy, L. A., Pink, R. C. & Carter, D. R. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).

    Article  CAS  Google Scholar 

  18. Augustine, D. et al. Dynamic release and clearance of circulating microparticles during cardiac stress. Circ. Res. 114, 109–113 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Dasgupta, S. K. et al. Lactadherin and clearance of platelet-derived microvesicles. Blood 113, 1332–1339 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dasgupta, S. K., Le, A., Chavakis, T., Rumbaut, R. E. & Thiagarajan, P. Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium. Circulation 125, 1664–1672 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Ratajczak, M. Z. & Ratajczak, J. Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clin. Transl. Med. 5, 7 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980 (2013).

    Article  PubMed  CAS  Google Scholar 

  23. Nordin, J. Z. et al. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomedicine 11, 879–883 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Chevillet, J. R. et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl Acad. Sci. USA 111, 14888–14893 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D. & Remaley, A. T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Castoldi, M., Kordes, C., Sawitza, I. & Haussinger, D. Isolation and characterization of vesicular and non-vesicular microRNAs circulating in sera of partially hepatectomized rats. Sci. Rep. 6, 31869 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wiklander, O. P. et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles 4, 26316 (2015).

    Article  PubMed  Google Scholar 

  29. Willekens, F. L. et al. Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood 105, 2141–2145 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Al Faraj, A. et al. Endothelial cell-derived microparticles loaded with iron oxide nanoparticles: feasibility of MR imaging monitoring in mice. Radiology 263, 169–178 (2012).

    Article  PubMed  Google Scholar 

  31. Happonen, K. E. et al. The Gas6–Axl protein interaction mediates endothelial uptake of platelet microparticles. J. Biol. Chem. 291, 10586–10601 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Svensson, K. J. et al. Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J. Biol. Chem. 288, 17713–17724 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tian, T. et al. Dynamics of exosome internalization and trafficking. J. Cell. Physiol. 228, 1487–1495 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Fitzner, D. et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J. Cell Sci. 124, 447–458 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Tian, T. et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 289, 22258–22267 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. del Conde, I. et al. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler. Thromb. Vasc. Biol. 25, 1065–1070 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Parolini, I. et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 284, 34211–34222 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng, D. et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic 11, 675–687 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Soares, A. R. et al. Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci. Rep. 5, 13243 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Heusermann, W. et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J. Cell Biol. 213, 173–184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bobryshev, Y. V., Killingsworth, M. C. & Orekhov, A. N. Increased shedding of microvesicles from intimal smooth muscle cells in athero-prone areas of the human aorta: implications for understanding of the predisease stage. Pathobiology 80, 24–31 (2013).

    Article  PubMed  Google Scholar 

  42. Leroyer, A. S. et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J. Am. Coll. Cardiol. 49, 772–777 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Mayr, M. et al. Proteomics, metabolomics, and immunomics on microparticles derived from human atherosclerotic plaques. Circ. Cardiovasc. Genet. 2, 379–388 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Amabile, N., Rautou, P. E., Tedgui, A. & Boulanger, C. M. Microparticles: key protagonists in cardiovascular disorders. Semin. Thromb. Hemost. 36, 907–916 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Perrotta, I. & Aquila, S. Exosomes in human atherosclerosis: an ultrastructural analysis study. Ultrastruct. Pathol. 40, 101–106 (2016).

    Article  PubMed  Google Scholar 

  46. Arteaga, R. B. et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am. J. Cardiol. 98, 70–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Amabile, N. et al. Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham Heart Study. Eur. Heart J. 35, 2972–2979 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gordon, C. et al. Circulating endothelial microparticles as a measure of early lung destruction in cigarette smokers. Am. J. Respir. Crit. Care Med. 184, 224–232 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Heiss, C. et al. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J. Am. Coll. Cardiol. 51, 1760–1771 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Li, C. J., Liu, Y., Chen, Y., Yu, D., Williams, K. J. & Liu, M. L. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am. J. Pathol. 182, 1552–1562 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ferreira, A. C. et al. Postprandial hypertriglyceridemia increases circulating levels of endothelial cell microparticles. Circulation 110, 3599–3603 (2004).

    Article  PubMed  Google Scholar 

  52. Koga, H. et al. Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease. Eur. Heart J. 27, 817–823 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Diamant, M. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 106, 2442–2447 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Nomura, S. et al. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 116, 235–240 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Koga, H. et al. Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J. Am. Coll. Cardiol. 45, 1622–1630 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Sabatier, F. et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes 51, 2840–2845 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Preston, R. A. et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 41, 211–217 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Nomura, S., Shouzu, A., Omoto, S., Nishikawa, M. & Iwasaka, T. Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. Clin. Appl. Thromb. Hemost. 10, 133–141 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Chironi, G. et al. Circulating leukocyte-derived microparticles predict subclinical atherosclerosis burden in asymptomatic subjects. Arterioscler. Thromb. Vasc. Biol. 26, 2775–2780 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Suades, R., Padro, T., Vilahur, G. & Badimon, L. Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques. Thromb. Haemost. 108, 1208–1219 (2012).

    Article  PubMed  Google Scholar 

  61. Suades, R., Padro, T., Alonso, R., Mata, P. & Badimon, L. High levels of TSP1+/CD142+ platelet-derived microparticles characterise young patients with high cardiovascular risk and subclinical atherosclerosis. Thromb. Haemost. 114, 1310–1321 (2015).

    Article  PubMed  Google Scholar 

  62. Barry, O. P., Pratico, D., Savani, R. C. & FitzGerald, G. A. Modulation of monocyte-endothelial cell interactions by platelet microparticles. J. Clin. Invest. 102, 136–144 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mesri, M. & Altieri, D. C. Endothelial cell activation by leukocyte microparticles. J. Immunol. 161, 4382–4387 (1998).

    CAS  PubMed  Google Scholar 

  64. Mesri, M. & Altieri, D. C. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J. Biol. Chem. 274, 23111–23118 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Nomura, S. et al. High-shear-stress-induced activation of platelets and microparticles enhances expression of cell adhesion molecules in THP-1 and endothelial cells. Atherosclerosis 158, 277–287 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Njock, M. S. et al. Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs. Blood 125, 3202–3212 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Agouni, A. et al. Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Am. J. Pathol. 173, 1210–1219 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Amabile, N. et al. Circulating endothelial microparticles are associated with vascular dysfunction in patients with end-stage renal failure. J. Am. Soc. Nephrol. 16, 3381–3388 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Boulanger, C. M. et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104, 2649–2652 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Brodsky, S. V., Zhang, F., Nasjletti, A. & Goligorsky, M. S. Endothelium-derived microparticles impair endothelial function in vitro. Am. J. Physiol. Heart Circ. Physiol. 286, H1910–H1915 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Densmore, J. C. et al. Endothelium-derived microparticles induce endothelial dysfunction and acute lung injury. Shock 26, 464–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Jansen, F. et al. High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation. Cardiovasc. Res. 98, 94–106 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Dean, W. L., Lee, M. J., Cummins, T. D., Schultz, D. J. & Powell, D. W. Proteomic and functional characterisation of platelet microparticle size classes. Thromb. Haemost. 102, 711–718 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Edrissi, H., Schock, S. C., Hakim, A. M. & Thompson, C. S. Microparticles generated during chronic cerebral ischemia increase the permeability of microvascular endothelial barriers in vitro. Brain Res. 1634, 83–93 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Marcos-Ramiro, B. et al. Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function. BMC Neurosci. 15, 110 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Huber, J. et al. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler. Thromb. Vasc. Biol. 22, 101–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Mause, S. F., von Hundelshausen, P., Zernecke, A., Koenen, R. R. & Weber, C. Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler. Thromb. Vasc. Biol. 25, 1512–1518 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Rautou, P. E. et al. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ. Res. 108, 335–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Fink, K. et al. Selenium prevents microparticle-induced endothelial inflammation in patients after cardiopulmonary resuscitation. Crit. Care 19, 58 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Curtis, A. M. et al. p38 mitogen-activated protein kinase targets the production of proinflammatory endothelial microparticles. J. Thromb. Haemost. 7, 701–709 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Soleti, R. et al. Microparticles harboring Sonic Hedgehog promote angiogenesis through the upregulation of adhesion proteins and proangiogenic factors. Carcinogenesis 30, 580–588 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Jansen, F. et al. Endothelial microparticles reduce ICAM-1 expression in a microRNA-222-dependent mechanism. J. Cell. Mol. Med. 19, 2202–2214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Forlow, S. B., McEver, R. P. & Nollert, M. U. Leukocyte–leukocyte interactions mediated by platelet microparticles under flow. Blood 95, 1317–1323 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Zu, L. et al. Endothelial microparticles after antihypertensive and lipid-lowering therapy inhibit the adhesion of monocytes to endothelial cells. Int. J. Cardiol. 202, 756–759 (2016).

    Article  PubMed  Google Scholar 

  85. Keyel, P. A., Tkacheva, O. A., Larregina, A. T. & Salter, R. D. Coordinate stimulation of macrophages by microparticles and TLR ligands induces foam cell formation. J. Immunol. 189, 4621–4629 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Zakharova, L., Svetlova, M. & Fomina, A. F. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor. J. Cell. Physiol. 212, 174–181 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Yahagi, K. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat. Rev. Cardiol. 13, 79–98 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Boing, A. N., Hau, C. M., Sturk, A. & Nieuwland, R. Platelet microparticles contain active caspase 3. Platelets 19, 96–103 (2008).

    Article  PubMed  CAS  Google Scholar 

  89. Distler, J. H. et al. The release of microparticles by apoptotic cells and their effects on macrophages. Apoptosis 10, 731–741 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Huber, L. C. et al. The role of membrane lipids in the induction of macrophage apoptosis by microparticles. Apoptosis 12, 363–374 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Abid Hussein, M. N. et al. Cell-derived microparticles contain caspase 3 in vitro and in vivo. J. Thromb. Haemost. 3, 888–896 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Pizzirani, C. et al. Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. Blood 109, 3856–3864 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Sarkar, A., Mitra, S., Mehta, S., Raices, R. & Wewers, M. D. Monocyte derived microvesicles deliver a cell death message via encapsulated caspase-1. PLoS ONE 4, e7140 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Llorente-Cortes, V., Otero-Vinas, M., Camino-Lopez, S., Llampayas, O. & Badimon, L. Aggregated low-density lipoprotein uptake induces membrane tissue factor procoagulant activity and microparticle release in human vascular smooth muscle cells. Circulation 110, 452–459 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Pakala, R. Serotonin and thromboxane A2 stimulate platelet-derived microparticle-induced smooth muscle cell proliferation. Cardiovasc. Radiat. Med. 5, 20–26 (2004).

    Article  PubMed  Google Scholar 

  97. Weber, A., Koppen, H. O. & Schror, K. Platelet-derived microparticles stimulate coronary artery smooth muscle cell mitogenesis by a PDGF-independent mechanism. Thromb. Res. 98, 461–466 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Brousseau, C., Morissette, G., Fortin, J. P., Marceau, F. & Petitclerc, E. Tumor cells expressing tissue factor influence the migration of smooth muscle cells in a catalytic activity-dependent way. Can. J. Physiol. Pharmacol. 87, 694–701 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Shan, Z. et al. An endocrine genetic signal between blood cells and vascular smooth muscle cells: role of microRNA-223 in smooth muscle function and atherogenesis. J. Am. Coll. Cardiol. 65, 2526–2537 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hergenreider, E. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat. Cell Biol. 14, 249–256 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Zhou, J. et al. Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ. Res. 113, 40–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jansen, F. et al. MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary artery disease. J. Am. Heart Assoc. 3, e001249 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Sinning, J. M. et al. Circulating CD31+/Annexin V+ microparticles correlate with cardiovascular outcomes. Eur. Heart J. 32, 2034–2041 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Werner, N., Wassmann, S., Ahlers, P., Kosiol, S. & Nickenig, G. Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 26, 112–116 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Bernal-Mizrachi, L. et al. High levels of circulating endothelial microparticles in patients with acute coronary syndromes. Am. Heart J. 145, 962–970 (2003).

    Article  PubMed  Google Scholar 

  106. Nozaki, T. et al. Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J. Am. Coll. Cardiol. 54, 601–608 (2009).

    Article  PubMed  Google Scholar 

  107. Lacroix, R. et al. Standardization of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J. Thromb. Haemost. 11, 1190–1193 (2013).

    Article  Google Scholar 

  108. Yuana, Y. et al. Handling and storage of human body fluids for analysis of extracellular vesicles. J. Extracell. Vesicles 4, 29260 (2015).

    Article  PubMed  CAS  Google Scholar 

  109. Otsuka, F., Sakakura, K., Yahagi, K., Joner, M. & Virmani, R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler. Thromb. Vasc. Biol. 34, 724–736 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kelly-Arnold, A. et al. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc. Natl Acad. Sci. USA 110, 10741–10746 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sangiorgi, G. et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J. Am. Coll. Cardiol. 31, 126–133 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Burke, P. A. et al. Pathophysiology of calcium deposition in coronary arteries. Herz 26, 239–244 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Huang, H. et al. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation 103, 1051–1056 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Nicholls, S. J. et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J. Am. Coll. Cardiol. 49, 263–270 (2007).

    Article  PubMed  Google Scholar 

  115. Vengrenyuk, Y. et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc. Natl Acad. Sci. USA 103, 14678–14683 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Criqui, M. H. et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA 311, 271–278 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Martin, S. S. et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the multi-ethnic study of atherosclerosis. Circulation 129, 77–86 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Hsu, J. J., Lim, J., Tintut, Y. & Demer, L. L. Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification. Heart 102, 1710–1715 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Buendia, P. et al. Endothelial microparticles mediate inflammation-induced vascular calcification. FASEB J. 29, 173–181 (2015).

    Article  CAS  PubMed  Google Scholar 

  120. Kapustin, A. N. et al. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ. Res. 116, 1312–1323 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Kapustin, A. N. et al. Calcium regulates key components of vascular smooth muscle cell-derived matrix vesicles to enhance mineralization. Circ. Res. 109, e1–e12 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. New, S. E. P. et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ. Res. 113, 72–77 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Reynolds, J. L. et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J. Am. Soc. Nephrol. 15, 2857–2867 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Hutcheson, J. D. et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat. Mater. 15, 335–343 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Goettsch, C. et al. Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. J. Clin. Invest. 126, 1323–1336 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  126. New, S. E. P. & Aikawa, E. Role of extracellular vesicles in de novo mineralization: an additional novel mechanism of cardiovascular calcification. Arterioscler. Thromb. Vasc. Biol. 33, 1753–1758 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mallat, Z. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99, 348–353 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Min, P. K. et al. Local increase in microparticles from the aspirate of culprit coronary arteries in patients with ST-segment elevation myocardial infarction. Atherosclerosis 227, 323–328 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Porto, I. et al. Intracoronary microparticles and microvascular obstruction in patients with ST elevation myocardial infarction undergoing primary percutaneous intervention. Eur. Heart J. 33, 2928–2938 (2012).

    Article  PubMed  Google Scholar 

  130. Morel, O., Toti, F., Morel, N. & Freyssinet, J. M. Microparticles in endothelial cell and vascular homeostasis: are they really noxious? Haematologica 94, 313–317 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Falati, S. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J. Exp. Med. 197, 1585–1598 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Merten, M., Pakala, R., Thiagarajan, P. & Benedict, C. R. Platelet microparticles promote platelet interaction with subendothelial matrix in a glycoprotein IIb/IIIa-dependent mechanism. Circulation 99, 2577–2582 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Srikanthan, S., Li, W., Silverstein, R. L. & McIntyre, T. M. Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J. Thromb. Haemost. 12, 1906–1917 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Michel, J.-B., Virmani, R., Arbustini, E. & Pasterkamp, G. Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur. Heart J. 32, 1977–1985 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Camus, S. M. et al. Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease. Blood 120, 5050–5058 (2012).

    Article  CAS  PubMed  Google Scholar 

  136. Camus, S. M. et al. Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease. Blood 125, 3805–3814 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Leroyer, A. S. et al. CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularization. J. Am. Coll. Cardiol. 52, 1302–1311 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Lacroix, R. et al. Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro. Blood 110, 2432–2439 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Marcos-Ramiro, B., Garcia-Weber, D. & Millan, J. TNF-induced endothelial barrier disruption: beyond actin and Rho. Thromb. Haemost. 112, 1088–1102 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Falk, E., Nakano, M., Bentzon, J. F., Finn, A. V. & Virmani, R. Update on acute coronary syndromes: the pathologists' view. Eur. Heart J. 34, 719–728 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Janiszewski, M. et al. Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: a novel vascular redox pathway. Crit. Care Med. 32, 818–825 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Lozito, T. P. & Tuan, R. S. Endothelial cell microparticles act as centers of matrix metalloproteinsase-2 (MMP-2) activation and vascular matrix remodeling. J. Cell. Physiol. 227, 534–549 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Martinez de Lizarrondo, S. et al. Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 32, 1477–1487 (2012).

    Article  CAS  PubMed  Google Scholar 

  144. Taraboletti, G. et al. Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am. J. Pathol. 160, 673–680 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gasser, O. et al. Characterisation and properties of ectosomes released by human polymorphonuclear neutrophils. Exp. Cell Res. 285, 243–257 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. Canault, M. et al. Microparticles of human atherosclerotic plaques enhance the shedding of the tumor necrosis factor-alpha converting enzyme/ADAM17 substrates, tumor necrosis factor and tumor necrosis factor receptor-1. Am. J. Pathol. 171, 1713–1723 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Folkesson, M. et al. Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms. Thromb. Haemost. 114, 1165–1174 (2015).

    Article  PubMed  Google Scholar 

  148. Aharon, A., Tamari, T. & Brenner, B. Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb. Haemost. 100, 878–885 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Mitra, S., Wewers, M. D. & Sarkar, A. Mononuclear phagocyte-derived microparticulate caspase-1 induces pulmonary vascular endothelial cell injury. PLoS ONE 10, e0145607 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Schock, S. C. et al. Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells. Biochem. Biophys. Res. Commun. 450, 912–917 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Narula, J. et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J. Am. Coll. Cardiol. 61, 1041–1051 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Otsuka, F., Joner, M., Prati, F., Virmani, R. & Narula, J. Clinical classification of plaque morphology in coronary disease. Nat. Rev. Cardiol. 11, 379–389 (2014).

    Article  PubMed  Google Scholar 

  153. Katopodis, J. N. et al. Platelet microparticles and calcium homeostasis in acute coronary ischemias. Am. J. Hematol. 54, 95–101 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Mallat, Z. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 101, 841–843 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Montoro-Garcia, S. et al. Small-size circulating microparticles in acute coronary syndromes: relevance to fibrinolytic status, reparative markers and outcomes. Atherosclerosis 227, 313–322 (2013).

    Article  CAS  PubMed  Google Scholar 

  156. Morel, O. et al. Sustained elevated amounts of circulating procoagulant membrane microparticles and soluble GPV after acute myocardial infarction in diabetes mellitus. Thromb. Haemost. 91, 345–353 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Zielinska, M. et al. Circulating endothelial microparticles in patients with acute myocardial infarction. Kardiol. Pol. 62, 531–542 (2005).

    PubMed  Google Scholar 

  158. van der Zee, P. M. et al. P-Selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction. Clin. Chem. 52, 657–664 (2006).

    Article  CAS  PubMed  Google Scholar 

  159. Giannopoulos, G. et al. Red blood cell and platelet microparticles in myocardial infarction patients treated with primary angioplasty. Int. J. Cardiol. 176, 145–150 (2014).

    Article  PubMed  Google Scholar 

  160. Biasucci, L. M. et al. Differences in microparticle release in patients with acute coronary syndrome and stable angina. Circ. J. 76, 2174–2182 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Stepien, E. et al. Number of microparticles generated during acute myocardial infarction and stable angina correlates with platelet activation. Arch. Med. Res. 43, 31–35 (2012).

    Article  PubMed  Google Scholar 

  162. Sarlon-Bartoli, G. et al. Plasmatic level of leukocyte-derived microparticles is associated with unstable plaque in asymptomatic patients with high-grade carotid stenosis. J. Am. Coll. Cardiol. 62, 1436–1441 (2013).

    Article  CAS  PubMed  Google Scholar 

  163. Abbas, M. et al. Endothelial microparticles from acute coronary syndrome patients induce premature coronary artery endothelial cells ageing and thrombogenicity: role of the Ang II/AT1 receptor/NADPH oxidase-mediated activation of MAPKs and PI3-kinase pathways. Circulation 135, 280–296 (2016).

    Article  PubMed  CAS  Google Scholar 

  164. Chiva-Blanch, G. et al. CD3+/CD45+ and SMA-alpha+ circulating microparticles are increased in individuals at high cardiovascular risk who will develop a major cardiovascular event. Int. J. Cardiol. 208, 147–149 (2016).

    Article  PubMed  Google Scholar 

  165. Tsiantoulas, D. et al. Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. J. Lipid Res. 56, 440–448 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Emanueli, C. et al. Coronary artery-bypass-graft surgery increases the plasma concentration of exosomes carrying a cargo of cardiac microRNAs: an example of exosome trafficking out of the human heart with potential for cardiac biomarker discovery. PLoS ONE 11, e0154274 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Bi, S. et al. Correlation between serum exosome derived miR-208a and acute coronary syndrome. Int. J. Clin. Exp. Med. 8, 4275–4280 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Matsumoto, S. et al. Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ. Res. 113, 322–326 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. de Hoog, V. C. et al. Serum extracellular vesicle protein levels are associated with acute coronary syndrome. Eur. Heart J. Acute Cardiovasc. Care 2, 53–60 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Brill, A., Dashevsky, O., Rivo, J., Gozal, Y. & Varon, D. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc. Res. 67, 30–38 (2005).

    Article  CAS  PubMed  Google Scholar 

  171. Vicencio, J. M. et al. Plasma exosomes protect the myocardium from ischemia-reperfusion injury. J. Am. Coll. Cardiol. 65, 1525–1536 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Lai, C. P. & Breakefield, X. O. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front. Physiol. 3, 228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lai, R. C., Chen, T. S. & Lim, S. K. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med. 6, 481–492 (2011).

    Article  PubMed  Google Scholar 

  174. Timmers, L. et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res. 1, 129–137 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Timmers, L. et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res. 6, 206–214 (2011).

    Article  PubMed  Google Scholar 

  176. Arslan, F. et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 10, 301–312 (2013).

    Article  CAS  PubMed  Google Scholar 

  177. Gnecchi, M. et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat. Med. 11, 367–368 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Gnecchi, M. et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J. 20, 661–669 (2006).

    Article  CAS  PubMed  Google Scholar 

  179. Kervadec, A. et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J. Heart Lung Transplant. 35, 795–807 (2016).

    Article  PubMed  Google Scholar 

  180. Lai, R. C. et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4, 214–222 (2010).

    Article  CAS  PubMed  Google Scholar 

  181. Chen, L. et al. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem. Biophys. Res. Commun. 431, 566–571 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).

    Article  CAS  Google Scholar 

  183. Gallet, R. et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehw240 (2016).

  184. Vader, P., Mol, E. A., Pasterkamp, G. & Schiffelers, R. M. Extracellular vesicles for drug delivery. Adv. Drug Deliv. Rev. 106, 148–156 (2016).

    Article  CAS  PubMed  Google Scholar 

  185. Ferguson, S. W. & Nguyen, J. Exosomes as therapeutics: the implications of molecular composition and exosomal heterogeneity. J. Control. Release 228, 179–190 (2016).

    Article  CAS  PubMed  Google Scholar 

  186. Zernecke, A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009).

    Article  PubMed  Google Scholar 

  187. Jansen, F. et al. Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles. Circulation 128, 2026–2038 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Mackie, A. R. et al. Sonic hedgehog-modified human CD34+ cells preserve cardiac function after acute myocardial infarction. Circ. Res. 111, 312–321 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Agouni, A. et al. Sonic hedgehog carried by microparticles corrects endothelial injury through nitric oxide release. FASEB J. 21, 2735–2741 (2007).

    Article  CAS  PubMed  Google Scholar 

  190. Benameur, T., Soleti, R., Porro, C., Andriantsitohaina, R. & Martinez, M. C. Microparticles carrying Sonic hedgehog favor neovascularization through the activation of nitric oxide pathway in mice. PLoS ONE 5, e12688 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Goto, S. et al. Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity. J. Thromb. Haemost. 1, 2022–2030 (2003).

    Article  CAS  PubMed  Google Scholar 

  192. Shouzu, A. et al. Effect of ticlopidine on monocyte-derived microparticles and activated platelet markers in diabetes mellitus. Clin. Appl. Thromb. Hemost 10, 167–173 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Morel, O. et al. Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists. J. Thromb. Haemost. 2, 1118–1126 (2004).

    Article  CAS  PubMed  Google Scholar 

  194. Kagawa, H., Nomura, S., Nagahama, M., Ozaki, Y. & Fukuhara, S. Effect of ticlopidine on platelet-derived microparticles in patients with connective tissue diseases. Haemostasis 29, 255–261 (1999).

    CAS  PubMed  Google Scholar 

  195. Nomura, S., Shouzu, A., Omoto, S., Nishikawa, M. & Iwasaka, T. Benidipine improves oxidized LDL-dependent monocyte and endothelial dysfunction in hypertensive patients with type 2 diabetes mellitus. J. Hum. Hypertens. 19, 551–557 (2005).

    Article  CAS  PubMed  Google Scholar 

  196. Nomura, S. et al. The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients. Platelets 20, 16–22 (2009).

    Article  CAS  PubMed  Google Scholar 

  197. Nomura, S. et al. Effects of pitavastatin on monocyte chemoattractant protein-1 in hyperlipidemic patients. Blood Coagul. Fibrinolysis 20, 440–447 (2009).

    Article  CAS  PubMed  Google Scholar 

  198. Tramontano, A. F. et al. Statin decreases endothelial microparticle release from human coronary artery endothelial cells: implication for the Rho–kinase pathway. Biochem. Biophys. Res. Commun. 320, 34–38 (2004).

    Article  CAS  PubMed  Google Scholar 

  199. Diamant, M. et al. Simvastatin-induced endothelial cell detachment and microparticle release are prenylation dependent. Thromb. Haemost. 100, 489–497 (2008).

    Article  CAS  PubMed  Google Scholar 

  200. Huang, B. et al. Effect of 40 mg versus 10 mg of atorvastatin on oxidized low-density lipoprotein, high-sensitivity C-reactive protein, circulating endothelial-derived microparticles, and endothelial progenitor cells in patients with ischemic cardiomyopathy. Clin. Cardiol. 35, 125–130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Suades, R., Padro, T., Alonso, R., Mata, P. & Badimon, L. Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells. Thromb. Haemost. 110, 366–377 (2013).

    Article  CAS  PubMed  Google Scholar 

  202. Almquist, T., Mobarrez, F., Jacobson, S. H., Wallen, H. & Hjemdahl, P. Effects of lipid-lowering treatment on circulating microparticles in patients with diabetes mellitus and chronic kidney disease. Nephrol. Dial. Transplant. 31, 944–952 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Camargo, L. M. et al. Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy. Braz. J. Med. Biol. Res. 47, 432–437 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Mobarrez, F. et al. Release of endothelial microparticles in vivo during atorvastatin treatment; a randomized double-blind placebo-controlled study. Thromb. Res. 129, 95–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  205. Gerrits, A. J., Koekman, C. A., Yildirim, C., Nieuwland, R. & Akkerman, J. W. Insulin inhibits tissue factor expression in monocytes. J. Thromb. Haemost. 7, 198–205 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors were supported by Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, the Fondation de France 2012–00029497 (C.M.B.), ITMO-PMN-2016 (X.L.), Agence Nationale de la Recherche ANR-2016-Extrema (X.L.), ANR-2011-META-MiRA (C.M.B.), and ANR-Emergence-2012-MicroSpy (P.-E.R.).

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 970, Paris Cardiovascular Research Center – PARCC, 56 rue Leblanc, Paris, 75737, cedex 15, France

    Chantal M. Boulanger, Xavier Loyer, Pierre-Emmanuel Rautou & Nicolas Amabile

  2. Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, 56 rue Leblanc, Paris, 75737, cedex 15, France

    Chantal M. Boulanger & Xavier Loyer

  3. Service d'Hépatologie, DHU Unity Hôpital Beaujon, APHP, 100 boulevard du général Leclerc, 92100, Clichy, France

    Pierre-Emmanuel Rautou

  4. Université Denis Diderot-Paris 7, Sorbonne Paris Cité, 16 rue Henri Huchard, Paris, 75018, France

    Pierre-Emmanuel Rautou

  5. Cardiology Department, Institut Mutualiste Monsouris, 42 Boulevard Jourdan, Paris, 75014, France

    Nicolas Amabile

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C.M.B., X.L., and N.A. researched data for the article and wrote the manuscript. C.M.B. and P.-E.R. reviewed and edited the manuscript before submission. All authors provided substantial contribution to the discussion of content.

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Correspondence to Chantal M. Boulanger.

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C.M.B. and P.-E.R. have filed patents on the detection and biomarker use of microvesicles. The other authors declare no competing interests.

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Boulanger, C., Loyer, X., Rautou, PE. et al. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol 14, 259–272 (2017). https://doi.org/10.1038/nrcardio.2017.7

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