SUPPRESSION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 RELEASE FROM HUMAN CEREBRAL ENDOTHELIUM BY PLASMINOGEN ACTIVATORS - A FACTOR POTENTIALLY PREDISPOSING TO INTRACRANIAL BLEEDING

Background Intracranial bleeding is the most catastrophic potential co mplication of treatment with thrombolytic agents. To identify potentia l factors that may contribute to this problem, we characterized elabor ation by human brain endothelial cells of plasminogen activator inhibi tor-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 we re exposed to 10 to 1000 ng/mL recombinant tissue-type plasminogen act ivator (RTPA), urokinase-type plasminogen activator (UPA), or streptok inase/plasminogen (37 U streptokinase plus 2 mu mol/L plasminogen) for 24 hours, they exhibited concentration-dependent decreases in elabora tion of PAI-1 of 65+/-3%, 48+/-3%, and 59+/-8%. UPA and streptokinase/ plasminogen elicited decreases of 33+/-8% and 35+/-4%, respectively, t hat were specific with respect to the protease agonists as to total pr otein synthesis and cell type; ie, neither human umbilical vein endoth elial cells nor cerebral pericytes exhibited inhibition of PAI-1 elabo ration. No decrease in HCMEC PAI-I elaboration was induced by coagulat ion factor Xa (10 nmol/L). A 2.7+/-0.5-fold increase was induced by cu -thrombin (10 nmol/L). PAI-I secretion from HCMEC decreased within 4 h ours of exposure to 100 ng/mL RTPA. In HCMEC exposed to RTPA for 8 hou rs, PAI-1 mRNA decreased from 176+/-20 to 43+/-2.2 pg/mu g RNA. Conclu sions These results indicate that brain endothelial cells exposed to R TPA exhibit paradoxically diminished elaboration of PAI-1. This proper ty may render brain vasculature vulnerable to attack by serine proteas es, thereby predisposing to injury and initiating an underlying subseq uent intracerebral hemorrhage in patients given plasminogen activators for treatment of coronary thrombosis.