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Cardiovascular Research 2005 67(1):1-3; doi:10.1016/j.cardiores.2005.05.001
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Copyright © 2005, European Society of Cardiology

Dying for attention: Microparticles and angiogenesis

Chantal M. Boulanger* and Alain Tedgui

Cardiovascular Research Center INSERM Lariboisière, 75475 Paris cedex 10, France

* Corresponding author. Tel.: +33 1 4463 1864; fax: +33 1 4281 3128. Email address: chantal.boulanger{at}larib.inserm.fr

Received 28 April 2005; accepted 2 May 2005

See article by Brill et al. [18] (pages 30–38) in this issue.

Microparticles, which were initially described as cell dust, have revealed over the past few years several exciting and unexpected properties. Microparticles are submicron vesicles shed from plasma membranes following cell activation or apoptosis, whose protein and lipid profile may be considered as a snapshot of the phenotype of the cell they stem from. The molecular mechanisms of microparticle formation and shedding are not yet fully understood, but seem to involve the changes in the cytoskeleton and exposure of phosphatidylserine on the outer leaflet of the plasma membrane [1,2]. Nevertheless, microparticles can easily be generated in vitro from aggregating platelets or from cultured cells following activation or apoptosis.

Microparticles are also found circulating in the blood. Their numbers increase in patients exhibiting hypercoagulability and decrease in those with bleeding disorders [2,3]. Presence of microparticles has also been documented at sites of inflammation such as the acellular lipid core of the atherosclerotic plaque or the synovial fluid from patients with rheumatoid arthritis [3–6]. Furthermore, increased numbers of circulating microparticles have been reported in patients with acute coronary syndromes or other cardiovascular diseases [2,3,7]. Although platelet-derived microparticles appear to be a significant part of the number of circulating shed membrane vesicles, particles from other cell type such as red blood cells, leukocytes, or endothelial cells also contribute to the plasmatic pool. For example, circulating endothelial microparticles can be taken as a hallmark of stress-injured or dying endothelial cells and may be recognized in the future as a marker of endothelial dysfunction [8].

However, microparticles can no longer be described as the passive bystanders they were once thought to be, waiting to be removed by professional phagocytes. First of all, they express a pro-coagulant phenotype, by promoting phosphatidylserine-induced activation of blood-borne tissue factor or by triggering tissue factor expression on monocytes by a P-selectin-dependent pathway [1,2,9–11]. Interestingly, the thrombogenicity of the atherosclerotic plaque is fully determined by the presence of microparticles in the acellular lipid core [4,5,12]. Microparticles can also directly affect vascular endothelial cells by increasing leukocyte adhesion, triggering cytokine production, and exposing tissue factor or P-selectin [2,3,11]. In addition, microparticles promote endothelial dysfunction by impairing the endothelial NO pathway and inducing proinflammatory responses [3,13–16]. Although this effect has been observed in vitro with microparticles from different cellular origin, it appears to be mediated in vivo by circulating microparticles specifically derived from endothelial cells [8]. While standardization of methods for isolating and characterizing microparticles will be welcome [25,26], it has become clear that microparticles are actively involved in cellular control mechanisms.

All the effects reported so far for microparticles suggest specific interaction(s) with target cell membranes, but very little is known about the molecular mechanisms involved. Adhesion molecules, receptors involved in phagocytosis, and membrane fusion effects could all take part, but one of the most intriguing features of microparticles is their capacity to deliver proteins to cells that do not normally express them, and even to transfer biologically active lipids [2,3,17].

The elegant study by Brill et al. published in the present issue [18] convincingly adds to the notion that microparticles are active players by demonstrating that platelet-derived microparticles induce angiogenesis and improve revascularization after chronic ischemia in vivo. This work documents further the role of platelets initiated in their previous paper [19] and extends the study of Kim et al. showing that platelet-derived microparticles promote proliferation and survival of endothelial cells as well as tube formation [20]. In the current paper, Brill et al. demonstrate that microparticles generated from thrombin-activated platelets increase sprouting from isolated arterial rings in culture and stimulate endothelial cell invasion through a Matrigel layer in vitro [18]. In addition, they show that introducing platelet-derived microparticles under the skin in mice promotes the development of capillaries, and that injecting them in the ischemic heart muscle in rats increases revascularization, although it remains to be confirmed that in vivo formation of platelet-derived microparticles causes similar effects as those reported here.

The angiogenic effects of platelet-derived microparticles observed by Brill et al. were mediated by VEGF, released during platelet activation and possibly associated with the platelet microparticles [18,21], as well as by other growth factors such as bFGF and PDGF. As expected for a VEGF-mediated effect, the molecular mechanism of the angiogenesis initiated by platelet-derived microparticles involved the kinases ERK, PI 3-kinase, and Src. However, other regulators of angiogenesis known to be associated with microparticles, such as tissue factor, could also contribute to these effects, possibly by direct transfer from the microparticles to the target cells [9,22]. The angiogenic effects demonstrated in the present paper are probably not restricted to microparticles of platelet origin. Vesicles derived from tumor cells also promote tumor angiogenesis [23], and microparticles of endothelial origin may contribute to angiogenesis because of the matrix metalloprotease activities they carry [24].

The study by Brill et al. adds an exciting new milestone to microparticle research, introducing the challenging new concept that microparticles from stress-injured and dying cells could be a life-saving signal for ischemic tissues, alerting the body for special attention and the need for emergency repair procedures.


   Acknowledgements
 
The authors are part of the European Vascular Genomics Network (Contract N° LSHM-CT-2003-503254). CMB wishes to thank Dr. Charles H. Robert for stimulating discussion and the snappy title.


   References
Top
 References
 

  1. Zwaal R.F., Schroit A.J. Pathophysiologic implications of membrane phospholipid asymmetry in blood cells. Blood (1997) 89:1121–1132.[Free Full Text]
  2. Freyssinet J.M. Cellular microparticles: what are they bad or good for? J Thromb Haemost (2003) 1:1655–1662.[CrossRef][ISI][Medline]
  3. Van Wijk M.J., Van Bavel E., Sturk A., Nieuwland R. Microparticles in cardiovascular diseases. Cardiovasc Res (2003) 59:277–287.[Abstract/Free Full Text]
  4. Mallat Z., Tedgui A. Current perspective on the role of apoptosis in atherothrombotic disease. Circ Res (2001) 88:998–1003.[Abstract/Free Full Text]
  5. Mallat Z., Hugel B., Ohan J., Leseche G., Freyssinet J.M., 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. Berckmans R.J., Nieuwland R., Tak P.P., Boing A.N., Romijn F.P., Kraan M.C., et al. Cell-derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII-dependent mechanism. Arthritis Rheum (2002) 46:2857–2866.[CrossRef][ISI][Medline]
  7. Mallat Z., Benamer H., Hugel B., Benessiano J., Steg P.G., Freyssinet J.M., et al. 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]
  8. Amabile N., Guerin A., Boddaert J., Nguyen C., Mallat Z., London G., et al. Circulating microparticles from hemodialyzed patients induce endothelial NO dysfunction: association with endothelial but not platelet-derived microparticles (abstract). Hypertension (2004) 44:570.
  9. Biro E., Sturk-Maquelin K.N., Vogel G.M., Meuleman D.G., Smit M.J., Hack C.E., et al. Human cell-derived microparticles promote thrombus formation in vivo in a tissue factor-dependent manner. J Thromb Haemost (2003) 1:2561–2568.[CrossRef][ISI][Medline]
  10. Giesen P.L., Rauch U., Bohrmann B., Kling D., Roque M., Fallon J.T., et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A (1999) 96:2311–2315.[Abstract/Free Full Text]
  11. Wagner D.D. New links between inflammation and thrombosis. Arterioscler Thromb Vasc Biol (2005 (Apr 14)) 10.1161/01.ATV.0000166521.90532.44 [Epub ahead of print].
  12. Schecter A.D., Spirn B., Rossikhina M., Giesen P.L., Bogdanov V., Fallon J.T., et al. Release of active tissue factor by human arterial smooth muscle cells. Circ Res (2000) 87:126–132.[Abstract/Free Full Text]
  13. Boulanger C.M., Scoazec A., Ebrahimian T., Henry P., Mathieu E., Tedgui A., et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation (2001) 104:2649–2652.[Abstract/Free Full Text]
  14. Martin S., Tesse A., Hugel B., Martinez M.C., Morel O., Freyssinet J.M., et al. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation (2004) 109:1653–1659.[Abstract/Free Full Text]
  15. Barry O.P., Kazanietz M.G., Pratico D., FitzGerald G.A. Arachidonic acid in platelet microparticles up-regulates cyclooxygenase-2-dependent prostaglandin formation via a protein kinase C/mitogen-activated protein kinase-dependent pathway. J Biol Chem (1999) 274:7545–7556.[Abstract/Free Full Text]
  16. Brodsky S.V., Zhang F., Nasjletti A., Goligorsky M.S. Endothelium-derived microparticles impair endothelial function in vitro. Am J Physiol Heart Circ Physiol (2004) 286:H1910–H1915.[Abstract/Free Full Text]
  17. Barry O.P., Pratico D., Lawson J.A., Fitz Gerald G.A. Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles. J Clin Invest (1997) 99:2118–2127.[ISI][Medline]
  18. Brill A., Dashevsky O., Rivo J., Gozal Y., Varon D. Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization. Cardiovasc Res (2005) 67:30–38.[Abstract/Free Full Text]
  19. Brill A., Elinav H., Varon D. Differential role of platelet granular mediators in angiogenesis. Cardiovasc Res (2004) 63:226–235.[Abstract/Free Full Text]
  20. Kim H.K., Song K.S., Chung J.H., Lee K.R., Lee S.N. Platelet microparticles induce angiogenesis in vitro. Br J Haematol (2004) 124:376–384.[CrossRef][ISI][Medline]
  21. Arisato T., Hashiguchi T., Sarker K.P., Arimura K., Asano M., Matsuo K., et al. Highly accumulated platelet vascular endothelial growth factor in coagulant thrombotic region. J Thromb Haemost (2003) 1:2589–2593.[CrossRef][ISI][Medline]
  22. Belting M., Dorrell M.I., Sandgren S., Aguilar E., Ahamed J., Dorfleutner A., et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med (2004) 10:502–509.[CrossRef][ISI][Medline]
  23. Kim C.W., Lee H.M., Lee T.H., Kang C., Kleinman H.K., Gho Y.S. Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelin. Cancer Res (2002) 62:6312–6317.[Abstract/Free Full Text]
  24. Taraboletti G., D'Ascenzo S., Borsotti P., Giavazzi R., Pavan A., Dolo V. Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am J Pathol (2002) 160:673–680.[Abstract/Free Full Text]
  25. Jy W., Horstman L.L., Jimenez J.J., Ahn Y.S., Biro E., Nieuwland R., et al. Measuring circulating cell-derived microparticles. J Thromb Haemost (2004) 2:1842–1843.[CrossRef][ISI][Medline]
  26. Freyssinet J.M., Dignat-George F. More on: measuring circulating cell-derived microparticles. J Thromb Haemost (2005) 3:613–614.[CrossRef][ISI][Medline]

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C. M. Boulanger, N. Amabile, and A. Tedgui
Circulating Microparticles: A Potential Prognostic Marker for Atherosclerotic Vascular Disease
Hypertension, August 1, 2006; 48(2): 180 - 186.
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