Blood, 1 October 2007, Vol. 110, No. 7, pp. 2224-2225.
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HEMOSTASIS
Comment on Lacroix et al, page 2432
It's not size, it's substance
Edward F. Plow, and
Elzbieta Pluskota
CLEVELAND CLINIC
Lacroix and colleagues provide the first evidence that endothelium-derived microparticles provide an efficient surface for plasminogen activation in a urokinase-type plasminogen activator (uPA)–dependent and uPA receptor (uPAR)–dependent manner, and suggest that generated plasmin may influence angiogenesis.
Microparticles are usually defined as a heterogenous population of small (0.1-1 µm diameter) membrane-coated vesicles, which are released by all cell types upon activation or apoptosis. The first report of microparticles is ascribed to Wolf, who detected the presence of platelet-derived fragments in human plasma in 1967.1 For many years, the existence of microparticles continued to be acknowledged, but they were simply regarded as "cell dust." However, over the past decade it has become clear that these "dwarf cells" are much more than inert debris. As examples with particular relevance to hemostasis, detection of microparticles in blood is now accepted as a diagnostic and prognostic marker for cardiovascular disease,2 and both in vitro and in vivo studies implicate circulating microparticles in initiation and propagation of coagulation.3
Lacroix and colleagues now assign a new function to microparticles: they can express a profibrinolytic function, thereby complementing their procoagulant activity. These authors demonstrate that plasmin can be generated on the surface of microparticles derived from TNF- –stimulated endothelial cells. Employing many approaches including electron microscopy and fluorescence-activated cell sorting (FACS), the authors provide convincing evidence that endogenous uPA and uPAR are present on the microparticle surface and, furthermore, that engagement of uPAR by exogenous uPA on the microparticles enhances plasminogen activation. Plasminogen interacts with the microparticles via its lysine binding sites, and -enolase is identified as a pivotal receptor in mediating this interaction. Thus, the authors elegantly delineate the mechanism by which plasminogen is activated on the microparticle surface. This model does closely resembles the mechanism of plasminogen activation observed on cell surfaces, where plasminogen binding via a variety of its receptors is a prerequisite for its efficient activation,4 but we now know that this mechanism is operative to microparticles.
Plasmin has a broad substrate repertoire and is capable of degrading fibrin and extracellular matrix proteins, activating various matrix metalloproteases, and participating in cytokine and growth hormone processing. Thus, plasmin not only contributes to fibrinolysis and maintenance of vascular patency, but also is a critical regulator of cell migration and has been implicated in inflammation and angiogenesis. Lacroix and colleagues take the initial steps to implicate microparticles and their regulation of plasmin generation in angiogenesis by analyzing their effect on tube formation by endothelial progenitor cells in an in vitro assay. At low concentrations, microparticles slightly enhance the response, and at higher concentrations they inhibit tube formation. How this model system and the concentration-dependent effects translate to angiogenesis in vivo is a question that remains to be resolved. There are more questions: would endothelium-derived microparticles bind to fibrin and mediate clot dissolution? Do microparticles derived from other cell types also bind and enhance activation of plasminogen? More globally, are microparticles involved in plasmin generation in vivo? These questions now become relevant based on the findings of Lacroix and colleagues. Answers to these and other questions are not likely to be determined by the size of the microparticles, but by the substances that they carry on their surfaces.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol 1967; 13:269–288.[Medline]
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- Boulanger CM, Amabile N, Tedgui A. Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension 2006; 48:180–186.[Free Full Text]
- Morel O, Toti F, Hugel B, et al. Procoagulant microparticles. Disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol 2006; 26:2594–2604.[Abstract/Free Full Text]
- Plow EF, Herren T, Redlitz A, Miles LA, Hoover-Plow JL. The cell biology of the plasminogen system. FASEB J 1995; 9:939–945.[Abstract]
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Related Article in Blood Online:
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Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro
- Romaric Lacroix, Florence Sabatier, Agnès Mialhe, Agnès Basire, Ralph Pannell, Hélène Borghi, Stephane Robert, Edouard Lamy, Laurent Plawinski, Laurence Camoin-Jau, Victor Gurewich, Eduardo Angles-Cano, and Françoise Dignat-George
Blood 2007 110: 2432-2439.
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