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Circulation Research. 2000;87:81-82

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(Circulation Research. 2000;87:81.)
© 2000 American Heart Association, Inc.

Editorial

Smooth Muscle Cells

Another Source of Tissue Factor–Containing Microparticles in Atherothrombosis?

Alain Tedgui, Ziad Mallat

From the Institut National de la Santé et de la Recherche Médicale, INSERM U541 and Institut Fédératif de Recherche "Circulation Paris-7," Hôpital Lariboisière, Paris, France.

Correspondence to Alain Tedgui, PhD, INSERM U541, 41, Bd de la Chapelle, 75475 Paris Cedex 10, France. E-mail tedgui{at}infobiogen.fr


Key Words: muscle, smooth • thromboplastin • atherosclerosis • thrombosis • microparticles


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Severe clinical manifestations of atherosclerosis, including sudden death, myocardial infarction, and stroke, mainly result from atherosclerotic plaque rupture/erosion that triggers thrombus formation, leading to occlusion of the vessel lumen.1 The occluding thrombus is mixed in nature and contains significant quantities of fibrin in addition to platelets,2 suggesting an important role for the coagulation cascade in plaque thrombus formation. Tissue factor (TF), a 47-kDa transmembrane glycoprotein, is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity.3 4 5 Yet, the origin of active TF within the plaque has not been well established.

Analysis of coronary atherectomy specimens from patients with unstable angina showed a strong correlation between TF content and areas of macrophages and smooth muscle cells, suggesting cell-mediated thrombogenicity.6 However, the acellular lipid-rich core of an atherosclerotic plaque exhibits the most intense TF staining, and functional studies have shown that it represents the most thrombogenic part of the plaque.4 This suggests that plaque thrombogenicity is directly related to its extracellular TF content and that extracellular TF is responsible for a great majority of active TF in the plaque. We have recently shown that the enhanced activity of extracellular TF is directly related to the presence, in the lipid core, of TF-bearing–shed membrane microparticles that are rich in phosphatidylserine (PS).5 The microparticles could be identified by use of capture antibodies against specific surface antigens and appeared to originate mainly from macrophages and lymphocytes.5 These cells are known to be involved in microparticle shedding into the extracellular space on activation/apoptosis,7 8 a mechanism that has been previously proposed as a potential contributor to the dissemination of membrane-associated procoagulant activities.7 An accumulating body of evidence suggests that smooth muscle cells may also contribute to the generation of TF-containing microparticles in the lipid core. Indeed, smooth muscle cells can express TF at the cell membrane.9 Moreover, apoptotic bodies recovered from the supernatant of apoptotic plaque smooth muscle cells in culture are endowed with a procoagulant potential.10 However, the lack of specific markers for the smooth muscle cell surface did not allow the identification of a potential smooth muscle cell origin for the plaque microparticles.5 Therefore, the ability of smooth muscle cells to generate active TF in the surrounding milieu, especially in the absence of apoptotic death, was still unknown. In this issue of Circulation Research, Schecter and colleagues11 provide further insight into the possible origin of extracellular TF in atherosclerotic plaques. This group demonstrates for the first time that human smooth muscle cells can release active TF in the extracellular medium in the form of microparticles <=200 nm, similar to those found in the plaque lipid core. The study by Schecter et al clearly raises the possibility that some TF-bearing microparticles present within the atherosclerotic plaque are released from smooth muscle cells.

One of the important questions that follow from the present work is how TF-carrying microparticles are released from smooth muscle cells. Two different mechanisms are generally well accepted as triggers of membrane microparticle release: cell activation and cell apoptosis. Procoagulant activities were retrieved in microparticles shed from the plasma membrane of endotoxin-stimulated monocytes,7 ionophore-treated Epstein-Barr virus–infected B lymphocytes,12 or thrombin plus collagen or ionophore-activated platelets.13 Moreover, a direct relationship was established between the degree of apoptosis in cultured cells and the proportion of released microparticles stemming from surface blebs.8 14 15 In their study, Schecter et al11 observed a 3-fold increase in TF activity in the culture medium after stimulation with phorbol 12-myristate 13-acetate, platelet-derived growth factor, or tumor necrosis factor-{alpha}. However, the relative proportion of active TF released in the medium to that measured in cells remained constant at {approx}10% whatever the culture conditions. This finding indicates that the release of TF-containing microparticles from cultured smooth muscle cells was not a response to cell activation by these agonists. On the other hand, only 1% of smooth muscle cells underwent apoptosis in the present study, which led the authors to exclude the possibility that the released microparticles are apoptotic in nature. Therefore, it seems that the release of TF-containing microparticles from smooth muscle cells represents a constitutive property of these cells, at least in culture.

Another important question that follows from the present work is how TF released from smooth muscle cells can be active in the culture medium. TF activity is highly dependent on the presence of PS,16 which increases the catalytic efficiency of the TF/factor VIIa complex.17 In the present study, treatment with PS:phosphatidylcholine did not affect TF activity, which indicates that TF released from smooth muscle cells was in the appropriate PS-rich milieu. PS is predominantly located in membrane leaflets that face the cytosol and is redistributed on the cell surface during cell activation or apoptosis, conferring a potent procoagulant activity to the cell surface.7 12 18 However, the results of the present study argue against a role for cell activation in the generation of the appropriate PS-rich phospholipid milieu necessary for TF activation. Therefore, the mechanism responsible for PS externalization in smooth muscle cell–derived microparticles remains to be elucidated.

In summary, the emerging evidence that vascular cells can release membrane-bound active TF is important to our understanding of the pathobiology of atherothrombosis. We have recently reported that patients with acute coronary syndromes have elevated levels of circulating procoagulant microparticles.19 Moreover, there is some evidence that acute thrombosis may be initiated by membrane-bound circulating TF originating from monocytes and neutrophils.20 The important work by Schecter et al11 now provides evidence that extracellular TF present in the atherosclerotic plaques and blood-borne TF may also derive from microparticles released from smooth muscle cells. As previously shown for activated platelet-derived microparticles,21 microparticles released from smooth muscle cells or from other cell types are likely to carry bioactive metabolites, making them actors of transcellular communication or activation, or modulators of cell-cell interactions.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

(Circ Res. 2000;87:81-82.)


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999;353(suppl 2):SII5–SII9.
  2. Rentrop KP. Thrombi in acute coronary syndromes: revisited and revised. Circulation. 2000;101:1619–1626.[Free Full Text]
  3. Fernandez-Ortiz A, Badimon JJ, Falk E, Fuster V, Meyer B, Mailhac A, Weng D, Shah PK, Badimon L. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol. 1994;23:1562–1569.[Abstract]
  4. Toschi V, Gallo G, Lettino M, Fallon JT, Gertz SD, Fernandez-Ortiz A, Cheserbo JH, Badimon L, Nemerson Y, Fuster V, Badimon JJ. Tissue factor modulates thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599.[Abstract/Free Full Text]
  5. Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation. 1999;99:348–353.[Abstract/Free Full Text]
  6. Moreno PR, Bernardi VH, Lopezcuellar J, Murcia AM, Palacios IF, Gold HK, Mehran R, Sharma SK, Nemerson Y, Fuster V, Fallon JT. Macrophages, smooth muscle cells, and tissue factor in unstable angina: implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090–3097.[Abstract/Free Full Text]
  7. Satta N, Toti F, Feugeas O, Bohbot A, Dachary-Prigent J, Eschwège V, Hedman H, Freyssinet JM. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol. 1994;153:3245–3255.[Abstract]
  8. Aupeix K, Hugel B, Martin T, Bischoff P, Lill H, Pasquali JL, Freyssinet JM. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J Clin Invest. 1997;99:1546–1554.[Medline] [Order article via Infotrieve]
  9. Schecter AD, Giesen PL, Taby O, Rosenfield CL, Rossikhina M, Fyfe BS, Kohtz DS, Fallon JT, Nemerson Y, Taubman MB. Tissue factor expression in human arterial smooth muscle cells. TF is present in three cellular pools after growth factor stimulation. J Clin Invest. 1997;100:2276–2285.[Medline] [Order article via Infotrieve]
  10. Flynn PD, Byrne CD, Baglin TP, Weissberg PL, Bennett MR. Thrombin generation by apoptotic vascular smooth muscle cells. Blood. 1997;89:4378–4384.[Abstract/Free Full Text]
  11. Schecter AD, Spirn B, Rossikhinia M, Giesen PLA, Bogdanov V, Fallon JT, Fisher EA, Schnapp LM, Nemerson Y, Taubman MB. Release of active tissue factor by human arterial smooth muscle cells. Circ Res. 2000;87:126–132.[Abstract/Free Full Text]
  12. Aupeix K, Toti F, Satta N, Bischoff P, Freyssinet JM. Oxysterols induce membrane procoagulant activity in monocytic THP-1 cells. Biochem J. 1996;314:1027–1033.
  13. Zwaal RF, Schroit AJ. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood. 1997;89:1121–1132.[Free Full Text]
  14. Zhang J, Driscoll TA, Hannun YA, Obeid LM. Regulation of membrane release in apoptosis. Biochem J. 1998;334:479–485.
  15. Zhang J, Reedy MC, Hannun YA, Obeid LM. Inhibition of caspases inhibits the release of apoptotic bodies: Bcl-2 inhibits the initiation of formation of apoptotic bodies in chemotherapeutic agent-induced apoptosis. J Cell Biol. 1999;145:99–108.[Abstract/Free Full Text]
  16. Pei G, Powers DD, Lentz BR. Specific contribution of different phospholipid surfaces to the activation of prothrombin by the fully assembled prothrombinase. J Biol Chem. 1993;268:3226–3233.[Abstract/Free Full Text]
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  18. Casciola-Rosen LA, Rosen A, Petri M, Schlissel M. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A.. 1996;93:1624–1629.
  19. Mallat Z, Benamer H, Hugel B, Benessiano J, Steg PG, Freyssinet JM, Tedgui A. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation. 2000;101:841–843.[Abstract/Free Full Text]
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