Inhibition of vascular endothelial cell prostacyclin synthesis by plasmin
AI Schafer, R Rodriguez, J Loscalzo and MA Gimbrone
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Vascular endothelial cells (EC) play an active role in the synthesis and
assembly of components of the fibrinolytic system and the generation of the
major fibrinolytic protease plasmin. However, the reciprocal effects of
plasmin on EC function have not been previously examined. We have studied
the actions of plasmin on the production of prostacyclin (PGI2) by cultured
human umbilical vein (HUVEC) and bovine aortic (BAEC) endothelial cells.
Plasmin causes little or no direct stimulation of PGI2 formation by EC.
Preincubation of EC with plasmin, however, produces a time- and
concentration-dependent inhibition of ionophore A23187-, thrombin-, and
histamine-induced PGI2 synthesis; a smaller inhibitory effect on
arachidonate- and PGH2-induced PGI2 synthesis is found. Incubation of HUVEC
or BAEC with a physiologic concentration of plasminogen (180 micrograms/mL)
and recombinant tissue plasminogen activator (tPA) generates tPA
dose-dependent plasmin activity that exceeds that generated in the absence
of EC. In the presence of plasminogen, tPA also causes a tPA dose-dependent
inhibition of thrombin- and ionophore A23187-stimulated PGI2 production.
PGI2 inhibitory plasmin activity is generated within the concentration
range of tPA achieved in plasma during pharmacologic therapy with tPA.
These findings suggest that vascular endothelial cells not only regulate
activation of the fibrinolytic system but may also be targets of plasmin
action on PGI2 synthesis in the modulation of hemostasis and thrombosis.
Volume 74,
Issue 3,
pp. 1015-1020,
08/15/1989
Copyright © 1989 by The American Society of Hematology
