Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells

Anat Aharon; Tal Tamari; Benjamin Brenner

doi:10.1160/TH07-11-0691

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(05): 878-885
DOI: 10.1160/TH07-11-0691

Endothelium and Vascular Development

Schattauer GmbH

Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells

Anat Aharon

,

Tal Tamari

,

Benjamin Brenner

Abstract

als PDF herunterladen

Summary

Microvesicles (MVs) which include microparticles (MPs) and exosomes are found in blood circulation in normal physiologic conditions and are increased in a variety of diseases. This study evaluated the effects of MVs on human umbilical vein endothelial cells (HUVEC) by morphologic changes, apoptosis, and thrombogenicty, in vitro. Stimulation of monocyte cell line (THP-1) by starvation or by endotoxin and calcium ionophore A23187 resulted in the release of MVs which express exosome marker Tsg 101, negative phospholipids in their leaflets, monocyte markers (CD18, CD14) and active tissue factor (TF). MVs were found to disrupt EC integrity and rapidly induce membrane blebbing. Brief exposure (2–4 hours) to MVs resulted in EC membrane phospholipids “flip-flop” while longer stimulation (20 hours) led to two contradicting outcomes – tube formation as well as apoptosis, as assessed by nuclear fragmentation. Additionally, MVs exposure resulted in increased cell surface thrombogenicity and perturbation of the endothelial haemostatic balance, which were enhanced during longer exposure time. Activity, antigen level and mRNA expression of the coagulation initiator TF were elevated due to (i) adherence of MVs derived TF to the EC membrane, and (ii) an increase in endothelial TF expression. Furthermore, levels of the anticoagulant tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) were decreased. These findings demonstrate that monocyte MVs increase endothelial thrombogenicity and apoptosis. In addition, they induce tube formation which may indicate their angiogenic effect. These findings may clarify, in part, the role of MVs in EC dysfunction associated with inflammatory diseases and hypercoagulable states.

Keywords

Microparticles - endothelial cells - apoptosis - tissue factor - thrombogenicity

PDF (553 kb)

Referenzen

References
1 Piccin A, Murphy WG, Smith OP. Circulating microparticles: pathophysiology and clinical implications. Blood Rev 2007; 21: 157-171.
2 Caby MP, Lankar D, Vincendeau-Scherrer C. et al. Exosomal-like vesicles are present in human blood plasma. Int Immunol 2005; 17: 879-887.
3 Toth B, Lok CA, Böing A. et al. Microparticles and exosomes:impact on normal and complicated pregnancy. Am J Reprod Immunol 2007; 58: 389-402.
4 Keller S, Sanderson MP, Stoeck A. et al. Exosomes: from biogenesis and secretion to biological function. Immunol Lett 2006; 107: 102-8.
5 Simak J, Gelderman MP. Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers. Transfus Med Rev 2006; 20: 1-26.
6 Morel O, Morel N, Hugel B. et al. The significance of circulating microparticles in physiology, inflammatory and thrombotic diseases. Rev Med Interne 2005; 26: 791-801.
7 Mackman N, Tilley RE, Key NS. Role of the Extrinsic Pathway of Blood Coagulation in Hemostasis and Thrombosis. Arterioscler Thromb Vasc Biol 2007; 27: 1687-1693.
8 Furie B, Furie Bc. Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 2004; 10: 171-178.
9 Diamant M, Tushuizen ME, Sturk A. et al. Cellular microparticles: new players in the field of vascular disease?. Eur J Clin Invest 2004; 34: 392-401.
10 Martinez MC, Tesse A, Zobairi F. et al. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 2005; 288: H1004-1009.
11 Winn RK, Harlan JM. The role of endothelial cell apoptosis in inflammatory and immune diseases. J Thromb Haemost 2005; 03: 1815-1824.
12 Omoto S, Nomura S, Shouzu A. et al. Detection of monocyte-derived microparticles in patients with Type II diabetes mellitus. Diabetologia 2002; 45: 550-555.
13 Chirinos JA, Heresi GA, Velasquez H. et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboem-bolism. J Am Coll Cardiol 2005; 3; 45: 1467-1471.
14 Sabatier F, Roux V, Anfosso F. et al. Interaction of endothelial microparticles with monocytic cells in vitro induces tissue factor-dependent procoagulant activity. Blood 2002; 1; 99: 3962-3970.
15 Jaffe EA, Nachman RL, Becher GG. et al. Culture of endothelial cells derived from umbilical veins. J Clin Invest 1973; 52: 2745-2756.
16 Aharon A, Brenner B, Katz T. et al. Tissue factor and tissue factor pathway inhibitor levels in trophoblast cells: implications for placental hemostasis. Thromb Haemost 2004; 92: 776-786.
17 Del Conde I, Shrimpton CN, Thiagarajan P. et al. Tissue factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 2005; 106: 1604-1611.
18 Sinauridze EI, Kireev DA, Popenko NY. et al. Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007; 97: 425-434.
19 McDonald B, Martin-Serrano J. Regulation of Tsg101 Expression by the Steadiness Box: A Role of Tsg101-associated Ligase. Mol Biol Cell 2008; 19: 754-763.
20 Brill A, Dashevsky O, Rivo J. et al. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc Res 2005; 67: 30-38.
21 Essayagh S, Xuereb JM, Terrisse AD. et al. Microparticles from apoptotic monocytes induce transient platelet recruitment and tissue factor expression by cultured human vascular endothelial cells via a redox-sensitive mechanism. Thromb Haemost 2007; 98: 831-837.
22 Sinauridze EI, Kireev DA, Popenko NY. et al. Platelet microparticle membranes have 50– to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 2007; 97: 425-434.
23 Bach RR. Tissue factor encryption. Arterioscler Thromb Vasc Biol 2006; 26: 456-461.
24 Ratajczak J, Wysoczynski M, Hayek F. et al. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication Leukemia. 2006; 20: 1487-1495.
25 Mack M, Kleinschmidt A, Brühl H. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 2000; 06: 769-775.
26 Baj-Krzyworzeka M, Szatanek R, Weglarczyk K. et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 2006; 55: 808-818.
27 Rauch U, Bonderman D, Bohrmann B. et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood 2000; 96: 170-175.
28 Kim HK, Song KS, Chung JH, Lee KR, Lee SN. Platelet microparticles induce angiogenesis in vitro. Br J Haematol 2004; 124: 376-384.
29 Pradier A, Ettelaie C. The Influence of Exogenous Tissue Factor on the Regulators of Proliferation and Apoptosis in Endothelial Cells. J Vasc Res 2007; 45: 19-32.
30 Stefanec T. Endothelial Apoptosis could it have a role in the pathogenesis and treatment of disease?. Chest 2000; 117: 841-854.
31 Syntichaki P, Tavernarakis N. Death by necrosis. Uncontrollable catastrophe, or is there order behind the chaos?. EMBO Rep 2002; 03: 604-609.
32 Jansen S, Arning J, Beyersmann D. Effects of the Ca ionophore a23187 on zinc-induced apoptosis in C6 glioma cells. Biol Trace Elem Res 2003; 96: 133-142.
33 Mesri M, Altieri DC. Endothelial cell activation by leukocyte microparticles. J Immunol 1998; 161: 4382-4387.
34 Mesri M, Altieri DC. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem 1999; 274: 23111-23118.
35 Huber LC, Jungel A, Distler JH. et al. The role of membrane lipids in the induction of macrophage apoptosis by microparticles. Apoptosis 2007; 12: 363-374.
36 Bombeli T, Karsan A, Tait JF. et al. Apoptotic vascular endothelial cells become procoagulant. Blood 1997; 89: 2429-42 48.
37 Pradier A, Ettelaie C. The influence of exogenous tissue factor on the regulators of proliferation and apoptosis in endothelial cells. J Vasc Res 2007; 45: 19-32.
38 Abid Hussein MN, Böing AN, Sturk A. et al. Inhibition of microparticle release triggers endothelial cell apoptosis and detachment. Thromb Haemost 2007; 98: 1096-1107.
39 Morel O, Toti F, Hugel B. et al. Procoagulant microparticles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26: 2594-2604.
40 Morel O, Toti F, Bakouboula B. et al. Procoagulant microparticles: “criminal partners” in atherothrombosis and deleterious cellular exchanges. Pathophysiol Haemost Thromb 2006; 35: 15-22.
41 Hugel B, Martinez MC, Kunzelmann C. et al. Membrane microparticles: two sides of the coin. Physiology (Bethesda) 2005; 20: 22-27.
42 Dang CT, Magid MS, Weksler B. et al. Enhanced endothelial cell apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood 1999; 93: 1264-1270.
43 Winn RK, Harlan JM. The role of endothelial cell apoptosis in inflammatory and immune diseases. J Thromb Haemost 2005; 03: 1815-1824.
44 Morel O, Hugel B, Jesel L. et al. Procoagulant membranous microparticles and atherothrombotic complications in diabetics. Arch Mal Coeur Vaiss 2004; 97: 1006-1012.
45 Yulug E, Yenilmez E, Unsal MA. et al. Apoptotic and morphological features of the umbilical artery en-dothelium in mild and severe pre-eclampsia. Acta Ob-stet Gynecol Scand 2006; 85: 1038-1045.
46 Dignat-George F, Camoin-Jau L, Sabatier F. et al. Endothelial microparticles: a potential contribution to the thrombotic complications of the antiphospholipid syndrome. Thromb Haemost 2004; 91: 667-673.
47 Morel O, Jesel L, Freyssinet JM. et al. Elevated levels of procoagulant microparticles in a patient with myocardial infarction, antiphospholipid antibodies and multifocal cardiac thrombosis. Thromb J 2005; 03: 15.
48 Mallat Z, Benamer H, Hugel B. et al. Elevated levels of shed membrane microparticles with procoagu-lant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101: 841-843.
49 Tesselaar ME, Romijn FP, van der Linden IK. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis?. J Thromb Haemost 2007; 05: 520-527.
50 Hron G, Kollars M, Weber H. et al. Tissue factor-positive microparticles: cellular origin and association with coagulation activation in patients with colorectal cancer. Thromb Haemost 2007; 97: 119-123.
51 Pereira J, Alfaro G, Goycoolea M. et al. Circulating platelet-derived microparticles in systemic lupus erythematosus association with increased thrombin generation and procoagulant state. Thromb Haemost 2006; 95: 94-99.
52 Rectenwald JE, Myers Jr DD, Hawley AE. et al. D-dimer, P-selectin, and microparticles: novel markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005; 94: 312-317.
53 Chung J, Suzuki H, Tabuchi N. et al. Identification of tissue factor and platelet-derived particles on leukocytes during cardiopulmonary bypass by flow cytometry and immunoelectron microscopy. Thromb Hae-most 2007; 98: 368-374.