The cytoprotective signaling of EPCR-APC. EPCR-bound APC cleaves PAR1, and this PAR1 cleavage specifically activates Rac1 pathway, inhibits the activation of the nuclear factor-κB (NF-κB) pathway, and provides barrier protection. Cross-activation of the S1P1 by sphingosine kinase-1 stimulated by EPCR-APC activation of PAR1 may contribute to the EPCR-APC–mediated barrier protective effect and cell survival. FVIIa bound to EPCR can also cleave PAR1 and provide the barrier protective effect. However, mechanistic details involved in the FVIIa-EPCR–induced barrier protective effect are unknown. In contrast to EPCR-dependent PAR1 signaling, thrombin cleavage of PAR1 leads to RhoA activation and activation of nuclear factor-κB, leading to proinflammatory gene expression and barrier disruption. Various hypotheses were put forth on why EPCR-APC cleavage of PAR1 leads to cytoprotective signaling, whereas thrombin activation of PAR1 leads to proinflammatory response. These hypotheses have been discussed in the text.