This Article Full Text Full Text (PDF) All Versions of this Article: 106/18/2372    most recent 01.CIR.0000033972.90653.AFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brodsky, S. V. Articles by Goligorsky, M. S. Search for Related Content PubMed PubMed Citation Articles by Brodsky, S. V. Articles by Goligorsky, M. S. Pubmed/NCBI databases Substance via MeSH Related Collections Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation. 2002;106:2372.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Plasminogen Activator Inhibitor-1 Promotes Formation of Endothelial Microparticles With Procoagulant Potential

From the Department of Medicine (S.V.B., M.S.G.), New York Medical College, Valhalla, NY, and Departments of Surgery (K.M.), Pathology (M.G.), and Medicine (J.J.), State University of New York, Stony Brook, NY.

*Correspondence to Michael S. Goligorsky, MD, PhD, Department of Medicine/Nephrology, Basic Sciences Building, Room C-23, New York Medical College, Valhalla, NY 11595. E-mail michael_goligorsky{at}nymc.edu

Background— Endothelial dysfunction is emerging as a common denominator for diverse and highly prevalent cardiovascular diseases. Increased level of plasminogen activator inhibitor-1 (PAI-1) and procoagulant activity have been recognized as hallmarks of endothelial dysfunction. This study was aimed at investigating cellular actions of PAI-1 and a potential link between PAI-1 and procoagulant state.

Methods and Results— Human umbilical vein endothelial cells treated with PAI-1 were subjected to laser confocal fluorescence microscopy, immunoprecipitation and Western blotting, and FACS analysis for isolation and identification of endothelial microparticles. PAI-1 treatment resulted in a reduced expression of uPAR, its colocalization with caveolin, and the concomitant increase of uPAR abundance in the culture medium. FACS analysis revealed that PAI-1 rapidly and dose-dependently increased the number of endothelial microparticles expressing uPAR and _Vß₃ integrin. This process was attenuated by pretreatment with neutralizing anti-uPAR antibodies. PAI-1 knockout mice showed a significantly decreased number of circulating endothelial microparticles than wild-type mice; however, PAI-1–deficient animals responded to infusion of PAI-1 with a more pronounced rise in the number of microparticles. PAI-1 treatment increased the number of microparticles stained with Annexin V, evidence for the expression of anionic phospholipids. This was accompanied by the accelerated generation of thrombin.

Conclusions— The data disclose a novel effect of PAI-1 to dose-dependently promote formation of endothelial microparticles with the reduced transmembrane asymmetry of phospholipids. This phenomenon may be responsible for the observed increase in in vitro thrombin generation. These findings could potentially link these hallmarks of endothelial dysfunction—elevated levels of PAI-1 and propensity toward thrombosis.

Key Words: endothelium • urokinase • thrombosis

This article has been cited by other articles:

				R. Lacroix, F. Sabatier, A. Mialhe, A. Basire, R. Pannell, H. Borghi, S. Robert, E. Lamy, L. Plawinski, L. Camoin-Jau, et al. Activation of plasminogen into plasmin at the surface of endothelial microparticles: a mechanism that modulates angiogenic properties of endothelial progenitor cells in vitro Blood, October 1, 2007; 110(7): 2432 - 2439. [Abstract] [Full Text] [PDF]

				R. Zhao and G. X. Shen Involvement of Heat Shock Factor-1 in Glycated LDL-Induced Upregulation of Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells Diabetes, May 1, 2007; 56(5): 1436 - 1444. [Abstract] [Full Text] [PDF]

				O. Morel, F. Toti, B. Hugel, B. Bakouboula, L. Camoin-Jau, F. Dignat-George, and J.-M. Freyssinet Procoagulant Microparticles: Disrupting the Vascular Homeostasis Equation? Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2594 - 2604. [Abstract] [Full Text] [PDF]

				C. Sapet, S. Simoncini, B. Loriod, D. Puthier, J. Sampol, C. Nguyen, F. Dignat-George, and F. Anfosso Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2 Blood, September 15, 2006; 108(6): 1868 - 1876. [Abstract] [Full Text] [PDF]

				N. Werner, S. Wassmann, P. Ahlers, S. Kosiol, and G. Nickenig Circulating CD31+/Annexin V+ Apoptotic Microparticles Correlate With Coronary Endothelial Function in Patients With Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 112 - 116. [Abstract] [Full Text] [PDF]

				A. Mezentsev, R. M. H. Merks, E. O'Riordan, J. Chen, N. Mendelev, M. S. Goligorsky, and S. V. Brodsky Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1106 - H1114. [Abstract] [Full Text] [PDF]

				K. Al-Nedawi, J. Szemraj, and C. S. Cierniewski Mast Cell-Derived Exosomes Activate Endothelial Cells to Secrete Plasminogen Activator Inhibitor Type 1 Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1744 - 1749. [Abstract] [Full Text] [PDF]

				M. Perez-Casal, C. Downey, K. Fukudome, G. Marx, and C. H. Toh Activated protein C induces the release of microparticle-associated endothelial protein C receptor Blood, February 15, 2005; 105(4): 1515 - 1522. [Abstract] [Full Text] [PDF]

				A. C. Ferreira, A. A. Peter, A. J. Mendez, J. J. Jimenez, L. M. Mauro, J. A. Chirinos, R. Ghany, S. Virani, S. Garcia, L. L. Horstman, et al. Postprandial Hypertriglyceridemia Increases Circulating Levels of Endothelial Cell Microparticles Circulation, December 7, 2004; 110(23): 3599 - 3603. [Abstract] [Full Text] [PDF]

				S. V. Brodsky, F. Zhang, A. Nasjletti, and M. S. Goligorsky Endothelium-derived microparticles impair endothelial function in vitro Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1910 - H1915. [Abstract] [Full Text] [PDF]

				S. V. Brodsky, O. Gealekman, J. Chen, F. Zhang, N. Togashi, M. Crabtree, S. S. Gross, A. Nasjletti, and M. S. Goligorsky Prevention and Reversal of Premature Endothelial Cell Senescence and Vasculopathy in Obesity-Induced Diabetes by Ebselen Circ. Res., February 20, 2004; 94(3): 377 - 384. [Abstract] [Full Text] [PDF]

				T. T Keller, A. T.A Mairuhu, M. D de Kruif, S. K Klein, V. E.A Gerdes, H. ten Cate, D. P.M Brandjes, M. Levi, and E. C.M van Gorp Infections and endothelial cells Cardiovasc Res, October 15, 2003; 60(1): 40 - 48. [Abstract] [Full Text] [PDF]