Published online before print September 30, 2002, doi: 10.1161/01.CIR.0000033972.90653.AF
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(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
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