THROMBIN-INDUCED VASOSPASM - CELLULAR SIGNALING MECHANISMS

Background. In the setting of arterial injury, thrombin contributes to the hemostatic process by activating the coagulation cascade and plat elets. We hypothesized that thrombin also contributes to hemostasis by inducing vasospasm. The purpose of this investigation was to characte rize the cellular signaling mechanisms that modulate thrombin-induced vascular smooth muscle contractions. Methods. Contractile responses of intact bovine carotid artery smooth muscles were determined in a musc le bath. Contractile responses were correlated with phosphorylation ev ents as determined with whole cell phosphorylation and two-dimensional gel electrophoresis and with immunoblotting of glycerol-urea or two-d imensional gels. Results. Thrombin (1 to 1000 units/ml) induced sustai ned vascular smooth muscle contractions of similar magnitude as the po tent contractile agonist, endothelin. Thrombin-induced contractions we re associated with increases in the phosphorylation of the myosin ligh t chains (MLC20) and in the tyrosine phosphorylation of mitogen-activa ted protein kinase. Conclusions. These data suggest that thrombin is a potent physiologic contractile agonist that may modulate some forms o f vasospasm. Thrombin-induced contractions are associated with the act ivation of two cellular signaling pathways, the: myosin light chain ki nase and the mitogen-activated protein kinase pathways.