The cytoprotective protein C pathway for APC-mediated endothelial barrier protection. Protection of endothelial barrier function by APC requires EPCR and PAR-1.^43,46  Activation of PAR-1 by APC stimulates sphingosine kinase-1 (SphK-1) to form sphingosine-1-phosphate (S1P) from sphingosine.⁴³  S1P either released from activated platelets or formed intracellularly by SphK-1 activates the sphingosine-1-phosphate receptor 1 (S1P₁) to promote increased endothelial barrier protection. A direct interaction of EPCR with S1P₁ was postulated, but a mechanistic contribution to barrier protective effects remains unclear (indicated by question mark).⁴⁶  In addition to barrier protective effects, S1P also promotes cell survival. In contrast, ceramide and sphingosine contribute to signals inducing cell death. The dynamic equilibrium between the formation and degradation of ceramide, sphingosine, and S1P is a sphingolipid rheostat for the cell, and the setting of this rheostat balances death-initiating and death-preventing signaling. It is currently unclear whether the S1P cell survival signals contribute to APC antiapoptotic activity or other cytoprotective activities.