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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:903-911.)
© 1995 American Heart Association, Inc.

Articles

-Thrombin Stimulates Urokinase Production and DNA Synthesis in Cultured Human Cerebral Microvascular Endothelial Cells

Marie A. Shatos; Thomas Orfeo; Jacqueline M. Doherty; Paul L. Penar; Desire Collen; Kenneth G. Mann

From the Departments of Surgery (M.A.S., T.O., J.M.D., P.L.P.) and Biochemistry (M.A.S., D.C., K.G.M.), University of Vermont College of Medicine, Burlington, Vt, and the Center for Molecular and Vascular Biology (D.C.), Leuven, Belgium.

Correspondence to Marie A. Shatos, Department of Biochemistry, Given Bldg, Rm C-401, Burlington, VT 05405.

Abstract -Thrombin regulation of endothelial cell (EC) fibrinolysis has been documented by using endothelia derived from a number of anatomic locations but not with those derived from the human cerebral vasculature. In the present study, the fibrinolytic properties of human cerebral microvascular ECs and their regulation by -thrombin are delineated and contrasted with those of human umbilical vein and foreskin microvascular ECs. In cerebral ECs, -thrombin elicited a unique dose-dependent increase in urokinase production and DNA synthesis. Maximal stimulation, observed with 10 nmol/L -thrombin, resulted in a 30- to 50-fold increase in urokinase production and a concomitant fourfold increase in DNA synthesis; the increase in urokinase was reflected in higher steady-state levels of urokinase mRNA. The major urokinase product secreted is the single-chain form of the enzyme. No effect was observed with the addition of other proteases or catalytically inactive variants of -thrombin. A thrombin receptor agonist peptide upregulated urokinase production but had no effect on DNA synthesis, suggesting that fibrinolysis is mediated by the thrombin receptor but that proliferation is regulated by a different pathway. These findings suggest the possibility that the cerebral microvasculature may be a specialized region of the vascular system in which urokinase-type plasminogen activator, not tissue-type plasminogen activator, is the key catalyst of fibrin lysis when the brain responds to thrombotic events and that -thrombin may regulate repair of the cerebral microvascular system.

Key Words: thrombin • brain • endothelial cells • urokinase

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