Figure 4.

The model of PAR-1 activation by APC and thrombin in the absence and presence of EPCR occupancy in endothelial cells. When EPCR is not occupied, both PAR-1 and EPCR are associated with caveolin-1 in lipid-rafts of endothelial cells (8). In this case, the thrombin activation of PAR-1 signals via G_q and/or G_12/13, thereby enhancing the cellular permeability through the activation of RhoA and eliciting proinflammatory responses through activation of NF-κB. When EPCR is occupied by protein C, the receptor dissociates from caveolin-1, thereby coupling PAR-1 to the G_i subfamily of G-proteins (8). In this case, the activation of PAR-1 by thrombin increases the barrier integrity by activating Rac1 GTPase and elicits an antiinflammatory response by inhibiting NF-κB. The EPCR- and PAR-1-dependent protective response of thrombin via G_i-protein may be a direct effect or mediated through the transactivation of S1P₁ as has been described for APC (12, 15). See the text for more details. PC, protein C; Cav-1, caveolin-1; Th, thrombin; S1P, sphingosine 1-phosphate; S1P₁, sphingosine 1-phosphate receptor.