Inhibition of vascular endothelial cell prostacyclin synthesis by plasmin.
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.
Schafer
A I
AI
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.
Rodriguez
R
R
Loscalzo
J
J
Gimbrone
M A
MA
D000818:Animals; D001013:Aorta, Thoracic; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011464:Epoprostenol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005341:Fibrinolysin / Q000378:metabolism / Q000494:pharmacology*; D005342:Fibrinolysis; D006801:Humans; D010958:Plasminogen / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014471:Umbilical Veins
D010958:Plasminogen; D011464:Epoprostenol; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin