ALPHA-THROMBIN STIMULATES UROKINASE PRODUCTION AND DNA-SYNTHESIS IN CULTURED HUMAN CEREBRAL MICROVASCULAR ENDOTHELIAL-CELLS

alpha-Thrombin regulation of endothelial cell (EC) fibrinolysis has be en documented by using endothelia derived from a number of anatomic lo cations 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 alpha-thrombin are delineate d and contrasted with those of human umbilical vein and foreskin micro vascular ECs. In cerebral ECs, alpha-thrombin elicited a unique dose-d ependent increase in urokinase production and DNA synthesis. Maximal s timulation, observed with 10 nmol/L alpha-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 pro duct secreted is the single-chain form of the enzyme. No effect was ob served with the addition of other proteases or catalytically inactive variants of alpha-thrombin. A thrombin receptor agonist peptide upregu lated urokinase production but had no effect on DNA synthesis, suggest ing that fibrinolysis is mediated by the thrombin receptor but that pr oliferation is regulated by a different pathway. These findings sugges t the possibility that the cerebral microvasculature may be a speciali zed 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 alpha-thrombin may regulate repair of the cerebral microvascular syste m.