Microvesicles from platelets: novel drivers of vascular inflammation

Summary

Microvesicles are receiving increased attention not only as biomarkers but also as mediators of cell communication and as integral effectors of disease. Platelets present a major source of microvesicles and release these microvesicles either spontaneously or upon activation. Platelet-derived microvesicles retain many features of their parent cells and have been shown to exert modulatory effects on vascular and immune cells. Accordingly, microvesicles from platelets can be measured at increased levels in patients with cardiovascular disease or individuals at risk. In addition, isolated microvesicles from platelets were shown to exert immunomodulatory actions on various cell types. In this review the various aspects of platelet-derived microvesicles including release, clearance, measurement, occurrence during disease and relevance for the pathophysiology of vascular inflammation will be discussed.

Keywords

Platelet - microvesicle - microparticle - vascular inflammation - atherosclerosis

• References

• 1 Mause SF. et al. Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 2005; 25: 1512-1518.
• 2 Mause SF, Weber C. Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 2010; 107: 1047-1057.
• 3 Thery C. et al. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 2009; 09: 581-593.
• 4 Rondina MT. et al. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res 2013; 112: 1506-1519.
• 5 Andonegui G. et al. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417-2423.
• 6 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
• 7 Wong CH. et al. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol 2013; 14: 785-792.
• 8 Gawaz M. et al. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
• 9 Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res 2005; 96: 612-616.
• 10 Langer HF. et al. Platelets contribute to the pathogenesis of experimental auto-immune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
• 11 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
• 12 Lievens D. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327.
• 13 Lindemann S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490.
• 14 Gawaz M. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148: 75-85.
• 15 Huo Y. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
• 16 Koenen RR. et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med 2009; 15: 97-103.
• 17 Grommes J. et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012; 185: 628-636.
• 18 Weyrich AS. et al. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest 1995; 95: 2297-2303.
• 19 Theilmeier G. et al. Circulating activated platelets assist THP-1 monocytoid/endothelial cell interaction under shear stress. Blood 1999; 94: 2725-2734.
• 20 da Costa Martins P. et al. Platelet-monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation. Arterioscler Thromb Vasc Biol 2004; 24: 193-199.
• 21 Postea O. et al. Contribution of platelet CX(3)CR1 to platelet-monocyte complex formation and vascular recruitment during hyperlipidemia. Arterioscler Thromb Vasc Biol 2012; 32: 1186-1193.
• 22 Hu H. et al. Platelets enhance lymphocyte adhesion and infiltration into arterial thrombus. Thromb Haemost 2010; 104: 1184-1192.
• 23 Spectre G. et al. Platelets selectively enhance lymphocyte adhesion on subendothelial matrix under arterial flow conditions. Thromb Haemost 2012; 108: 328-337.
• 24 Naik MU. et al. JAM-A protects from thrombosis by suppressing integrin alphaIIbbeta3-dependent outside-in signaling in platelets. Blood 2012; 119: 3352-3360.
• 25 Karshovska E. et al. Hyperreactivity of junctional adhesion molecule a-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ Res 2015; 116: 587-599.
• 26 Liu F. et al. Mitochondrially mediated integrin alphaIIbbeta3 protein inactivation limits thrombus growth. J Biol Chem 2013; 288: 30672-30681.
• 27 Jobe SM. et al. Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis. Blood 2008; 111: 1257-1265.
• 28 Zhang Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464: 104-107.
• 29 Boudreau LH. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 2014; 124: 2173-2183.
• 30 Morel O. et al. Mechanisms of microparticle generation: on the trail of the mitochondrion!. Semin Thromb Hemost 2010; 36: 833-844.
• 31 Gemmell CH. et al. Platelet-derived microparticle formation involves glycoprotein IIb-IIIa. Inhibition by RGDS and a Glanzmann’s thrombasthenia defect. J Biol Chem 1993; 268: 14586-14589.
• 32 Sims PJ. et al. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem 1989; 264: 17049-17057.
• 33 Yano Y. et al. The effects of calpeptin (a calpain specific inhibitor) on agonist induced microparticle formation from the platelet plasma membrane. Thromb Res 1993; 71: 385-396.
• 34 Pasquet JM. et al. Calcium influx is a determining factor of calpain activation and microparticle formation in platelets. Eur J Biochem 1996; 239: 647-654.
• 35 Yano Y. et al. The role of protein phosphorylation and cytoskeletal reorganisation in microparticle formation from the platelet plasma membrane. Biochem J 1994; 299: 303-308.
• 36 Heijnen HF. et al. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 1999; 94: 3791-3799.
• 37 Kile BT. The role of apoptosis in megakaryocytes and platelets. Br J Haematol 2014; 165: 217-226.
• 38 Cauwenberghs S. et al. Shedding of procoagulant microparticles from unstimulated platelets by integrin-mediated destabilisation of actin cytoskeleton. FEBS Lett 2006; 580: 5313-5320.
• 39 Vasina EM. et al. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am J Blood Res 2013; 03: 107-123.
• 40 Montoro-Garcia S. et al. Small-size platelet microparticles trigger platelet and monocyte functionality and modulate thrombogenesis via P-selectin. Br J Haematol 2014; 166: 571-580.
• 41 Aatonen MT, Ohman T, Nyman TA. et al. Isolation and characterisation of platelet-derived extracellular vesicles. J Extracell Vesicles. 2014 Epub ahead of print.
• 42 Hergenreider E. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 2012; 14: 249-256.
• 43 Leroyer AS. et al. CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularisation. J Am Coll Cardiol 2008; 52: 1302-1311.
• 44 Loyer X. et al. Microvesicles as cell-cell messengers in cardiovascular diseases. Circ Res 2014; 114: 345-353.
• 45 Rand ML. et al. Rapid clearance of procoagulant platelet-derived microparticles from the circulation of rabbits. J Thromb Haemost 2006; 04: 1621-1623.
• 46 Rank A. et al. Clearance of platelet microparticles in vivo. Platelets 2011; 22: 111-116.
• 47 Dasgupta SK, Abdel-Monem H, Niravath P. et al. Lactadherin and clearance of platelet-derived microvesicles. Blood 2009; 113: 1332-1339.
• 48 Dasgupta SK. et al. Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium. Circulation 2012; 125: 1664-1672.
• 49 Yuana Y. et al. Pre-analytical and analytical issues in the analysis of blood micro-particles. Thromb Haemost 2011; 105: 396-408.
• 50 Dey-Hazra E. et al. Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing. Vasc Health Risk Manag 2010; 06: 1125-1133.
• 51 Shantsila E. et al. Circulating microparticles: challenges and perspectives of flow cytometric assessment. Thromb Haemost 2014; 111: 1009-1014.
• 52 Jy W. et al. Measuring circulating cell-derived microparticles. J Thromb Hae-most 2004; 02: 1842-1851.
• 53 Ayers L. et al. Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay. Thromb Res 2011; 127: 370-377.
• 54 van Ierssel SH. et al. Flow cytometric detection of endothelial microparticles (EMP): effects of centrifugation and storage alter with the phenotype studied. Thromb Res 2010; 125: 332-339.
• 55 Witwer KW. et al. Standardisation of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013 Epub ahead of print.
• 56 Gyorgy B. et al. Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting from shared biophysical parameters. Blood 2011; 117: e39-48.
• 57 Mobarrez F. et al. A multicolor flow cytometric assay for measurement of platelet-derived microparticles. Thromb Res 2010; 125: e110-116.
• 58 Berckmans RJ. et al. Cell-derived microparticles circulate in healthy humans and support low grade thrombin generation. Thromb Haemost 2001; 85: 639-646.
• 59 Chandler WL. Microparticle counts in platelet-rich and platelet-free plasma, effect of centrifugation and sample-processing protocols. Blood Coagul Fibrinolysis 2013; 24: 125-132.
• 60 Qiao JL. et al. Proteolysis of platelet receptors in humans and other species. Biol Chem 2010; 391: 893-900.
• 61 Lacroix R. et al. Overcoming limitations of microparticle measurement by flow cytometry. Semin Thromb Hemost 2010; 36: 807-818.
• 62 van der Vlist EJ. et al. Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nat Protoc 2012; 07: 1311-1326.
• 63 Lacroix R. et al. Standardisation of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 2010; 08: 2571-2574.
• 64 Thery C. et al. Isolation and characterisation of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006 Chapter 3: Unit 3 22.
• 65 Vogel R. et al. Quantitative sizing of nano/microparticles with a tunable elastomeric pore sensor. Anal Chem 2011; 83: 3499-3506.
• 66 Dragovic RA. et al. Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis. Nanomed 2011; 07: 780-788.
• 67 Bell NC. et al. Emerging techniques for submicrometer particle sizing applied to Stober silica. Langmuir 2012; 28: 10860-10872.
• 68 Varga Z. et al. Towards traceable size determination of extracellular vesicles. J Extracell Vesicles. 2014 Epub ahead of print.
• 69 Harapin J. et al. Structural analysis of supramolecular assemblies by cryo-electron tomography. Structure 2013; 21: 1522-1530.
• 70 Yuana Y. et al. Atomic force microscopy: a novel approach to the detection of nanosized blood microparticles. J Thromb Haemost 2010; 08: 315-323.
• 71 Ueba T. et al. Level, distribution and correlates of platelet-derived microparticles in healthy individuals with special reference to the metabolic syndrome. Thromb Haemost 2008; 100: 280-285.
• 72 Nielsen MH. et al. A flow cytometric method for characterisation of circulating cell-derived microparticles in plasma. J Extracell Vesicles. 2014 Epub ahead of print.
• 73 Amabile N. et al. Microparticles: key protagonists in cardiovascular disorders. Semin Thromb Hemost 2010; 36: 907-916.
• 74 Tan KT. et al. Platelet microparticles and soluble P selectin in peripheral artery disease: relationship to extent of disease and platelet activation markers. Ann Med 2005; 37: 61-66.
• 75 Namba M. et al. Circulating platelet-derived microparticles are associated with atherothrombotic events: a marker for vulnerable blood. Arterioscler Thromb Vasc Biol 2007; 27: 255-256.
• 76 van der Zee PM. et al. P-selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction. Clin Chem 2006; 52: 657-664.
• 77 Cohen Z. et al. Thrombin activity and platelet microparticle formation are increased in type 2 diabetic platelets: a potential correlation with caspase activation. Thromb Res 2002; 107: 217-221.
• 78 Trzepizur W. et al. Microparticles and vascular dysfunction in obstructive sleep apnoea. Eur Respir J 2014; 44: 207-216.
• 79 Sabatier F. et al. Type 1 and type 2 diabetic patients display different patterns of cellular microparticles. Diabetes 2002; 51: 2840-2845.
• 80 Preston RA. et al. Effects of severe hypertension on endothelial and platelet microparticles. Hypertension 2003; 41: 211-217.
• 81 Murakami T. et al. Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity. Thromb Res 2007; 119: 45-53.
• 82 Helal O. et al. Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress. Nutr Metab Cardiovasc Dis 2011; 21: 665-671.
• 83 Suades R. et al. Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells. Thromb Haemost 2013; 110: 366-377.
• 84 Suades R. et al. Circulating CD45+/CD3+ lymphocyte-derived microparticles map lipid-rich atherosclerotic plaques in familial hypercholesterolaemia patients. Thromb Haemost 2014; 111: 111-121.
• 85 Mobarrez F. et al. Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease. Thromb Haemost 2011; 106: 344-352.
• 86 Jayachandran M. et al. Characterisation of blood borne microparticles as markers of premature coronary calcification in newly menopausal women. Am J Physiol Heart Circ Physiol 2008; 295: H931-H938.
• 87 Mause SF. Platelet microparticles: reinforcing the hegemony of platelets in atherothrombosis. Thromb Haemost 2013; 109: 5-6.
• 88 Merten M. et al. Platelet microparticles promote platelet interaction with subendothelial matrix in a glycoprotein IIb/IIIa-dependent mechanism. Circulation 1999; 99: 2577-2582.
• 89 Suades R. et al. Circulating and platelet-derived microparticles in human blood enhance thrombosis on atherosclerotic plaques. Thromb Haemost 2012; 108: 1208-1219.
• 90 Agouni A. et al. Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Am J Pathol 2008; 173: 1210-1219.
• 91 Agouni A. et al. Microparticles from patients with metabolic syndrome induce vascular hypo-reactivity via Fas/Fas-ligand pathway in mice. PLoS one 2011; 6: e27809.
• 92 Hansson GK. et al. Detection of activated T lymphocytes in the human athero-sclerotic plaque. Am J Pathol 1989; 135: 169-175.
• 93 Sadallah S. et al. Ectosomes released by platelets induce differentiation of CD4+T cells into T regulatory cells. Thromb Haemost 2014; 112: 1219-1229.
• 94 Weber A. et al. Platelet-derived microparticles stimulate coronary artery smooth muscle cell mitogenesis by a PDGF-independent mechanism. Thromb Res 2000; 98: 461-466.
• 95 Butoi ED. et al. Cross talk between smooth muscle cells and monocytes/activated monocytes via CX3CL1/CX3CR1 axis augments expression of pro-atherogenic molecules. Biochim Biophys Acta 2011; 1813: 2026-2035.
• 96 Boilard E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327: 580-583.
• 97 Jancar S, Sanchez Crespo M. Immune complex-mediated tissue injury: a multi-step paradigm. Trends Immunol 2005; 26: 48-55.
• 98 Mayadas TN. et al. Mechanisms of immune complex-mediated neutrophil recruitment and tissue injury. Circulation 2009; 120: 2012-2024.
• 99 Nielsen CT. et al. Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation. Arthritis Rheum 2012; 64: 1227-1236.
• 100 van Eijk IC. et al. Circulating microparticles remain associated with complement activation despite intensive anti-inflammatory therapy in early rheumatoid arthritis. Ann Rheum Dis 2010; 69: 1378-1382.
• 101 Cloutier N. et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med 2013; 05: 235-249.
• 102 Rozmyslowicz T. et al. Platelet- and megakaryocyte-derived microparticles transfer CXCR4 receptor to CXCR4-null cells and make them susceptible to infection by X4-HIV. AIDS 2003; 17: 33-42.
• 103 Mause SF. et al. Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 2010; 122: 495-506.
• 104 Risitano A. et al. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood 2012; 119: 6288-6295.
• 105 Diehl P. et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc Res 2012; 93: 633-644.
• 106 Laffont B. et al. Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood 2013; 122: 253-261.
• 107 Barry OP. et al. Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest 1998; 102: 136-144.
• 108 Vasina EM. et al. Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis 2011; 02: e211.
• 109 Rautou PE. et al. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ Res 2011; 108: 335-343.
• 110 Sadallah S. et al. Microparticles (ectosomes) shed by stored human platelets downregulate macrophages and modify the development of dendritic cells. J Immunol 2011; 186: 6543-6552.
• 111 Vasina EM. et al. Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am J Blood Res 2013; 03: 107-123.
• 112 Faure V. et al. Elevation of circulating endothelial microparticles in patients with chronic renal failure. J Thromb Haemost 2006; 04: 566-573.
• 113 Vion AC. et al. Shear stress regulates endothelial microparticle release. Circ Res 2013; 112: 1323-1333.
• 114 Zernecke A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2009; 02: ra81.
• 115 Abid Hussein MN. et al. Phospholipid composition of in vitro endothelial microparticles and their in vivo thrombogenic properties. Thromb Res 2008; 121: 865-871.
• 116 Dignat-George F, Boulanger CM. The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol 2011; 31: 27-33.
• 117 Abid Hussein MN. et al. Inhibition of microparticle release triggers endothelial cell apoptosis and detachment. Thromb Haemost 2007; 98: 1096-1107.
• 118 Mezentsev A. et al. Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress. Am J Physiol Heart Circ Physiol 2005; 289: H1106-1114.
• 119 Leroyer AS. et al. Microparticles from ischemic muscle promotes postnatal vasculogenesis. Circulation 2009; 119: 2808-2817.
• 120 Habersberger J. et al. Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction. Cardiovasc Res 2012; 96: 64-72.
• 121 Wang JG. et al. Monocytic microparticles activate endothelial cells in an IL-1beta-dependent manner. Blood 2011; 118: 2366-2374.
• 122 Mallat Z. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 1999; 99: 348-353.
• 123 Leroyer AS. et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007; 49: 772-777.
• 124 Kapustin AN. et al. Vascular Smooth Muscle Cell Calcification is Mediated by Regulated Exosome Secretion. Circ Res 2015; 116: 1312-1323.