Vascular contraction and relaxation to thrombin and trypsin: thrombomodulin preferentially attenuates thrombin-induced contraction.

Thrombin and trypsin activate protease-activated receptors (PARs) that modulate vascular tone. In addition to the PARs, thrombin also binds to thrombomodulin via exosite 1, a domain also involved in the interaction of thrombin with PAR-1 but not PAR-2. The purpose of this study was to determine whether thrombomodulin would alter thrombin-induced vasoconstriction, thought to be mediated predominantly by PAR-1, but not PAR-2, which mediates vascular relaxation. For comparison, thrombomodulin was examined for its effect on both thrombin and trypsin-induced responses. Trypsin was 2000-fold more potent as a relaxant than as a contractile peptide, whereas thrombin was only 7.8-fold more potent as a relaxant than contractile agonist, consistent with activation of PAR-1 predominantly mediating contraction and PAR-2 predominantly mediating relaxation. Although thrombomodulin (10(-7) M) alone did not alter vascular tone or the rate of thrombin-induced vascular responses, thrombomodulin (10(-8) and 10(-7) M) attenuated maximal thrombin (10(-8) and 10(-7) M)-induced vasoconstriction preferentially compared with thrombin-induced relaxation and had no effect on equieffective trypsin-induced responses. The inhibition of thrombin-induced contraction resulted from the interaction of thrombin with thrombomodulin rather than any direct effect of thrombomodulin on tissue PARs. Thus, this study describes a novel vascular action of thrombomodulin to selectively attenuate thrombin-induced vascular contractility. This action of thrombomodulin may serve to protect vasculature from thrombin-induced vasoconstriction during conditions of endothelial injury known to increase plasma and cellular levels of thrombomodulin.