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(Circulation. 1996;94:636-642.)
© 1996 American Heart Association, Inc.

Articles

Suppression of Plasminogen Activator Inhibitor-1 Release From Human Cerebral Endothelium by Plasminogen Activators

A Factor Potentially Predisposing to Intracranial Bleeding

Marie A. Shatos, PhD; Jacqueline M. Doherty, BA; Paul L. Penar, MD; Burton E. Sobel, MD

the Departments of Biochemistry (M.A.S., J.M.D., B.E.S.), Medicine (B.E.S.), and Surgery, Division of Neurosurgery (P.L.P.), College of Medicine, University of Vermont, Burlington.

Correspondence to Marie A. Shatos, PhD, Department of Biochemistry, Given Bldg C401, Burlington, VT 05405.

Background Intracranial bleeding is the most catastrophic potential complication of treatment with thrombolytic agents. To identify potential factors that may contribute to this problem, we characterized elaboration by human brain endothelial cells of plasminogen activator inhibitor-1 (PAI-1) and measured PAI-1 mRNA levels.

Methods and Results When human cerebral microvascular endothelial cells (HCMEC), pial arterial endothelial cells, and middle meningeal arterial endothelial cells were exposed to 10 to 1000 ng/mL recombinant tissue-type plasminogen activator (RTPA), urokinase-type plasminogen activator (UPA), or streptokinase/plasminogen (37 U streptokinase plus 2 µmol/L plasminogen) for 24 hours, they exhibited concentration-dependent decreases in elaboration of PAI-1 of 65±3%, 48±3%, and 59±8%. UPA and streptokinase/plasminogen elicited decreases of 33±8% and 35±4%, respectively, that were specific with respect to the protease agonists as to total protein synthesis and cell type; ie, neither human umbilical vein endothelial cells nor cerebral pericytes exhibited inhibition of PAI-1 elaboration. No decrease in HCMEC PAI-1 elaboration was induced by coagulation factor Xa (10 nmol/L). A 2.7±0.5-fold increase was induced by -thrombin (10 nmol/L). PAI-1 secretion from HCMEC decreased within 4 hours of exposure to 100 ng/mL RTPA. In HCMEC exposed to RTPA for 8 hours, PAI-1 mRNA decreased from 176±20 to 43±2.2 pg/µg RNA.

Conclusions These results indicate that brain endothelial cells exposed to RTPA exhibit paradoxically diminished elaboration of PAI-1. This property may render brain vasculature vulnerable to attack by serine proteases, thereby predisposing to injury and initiating an underlying subsequent intracerebral hemorrhage in patients given plasminogen activators for treatment of coronary thrombosis.

Key Words: brain • endothelium • fibrinolysis

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