Activation of endothelial intrinsic NF-κB pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice

Although the role of systemic activation of the nuclear factor kappa B (NF-kappa B) pathway in septic coagulation has been well documented, little is known about the contribution of endothelial-specific NF-kappa B signaling in this pathologic process. Here, we used transgenic mice that conditionally overexpress a mutant I-kappa B alpha, an inhibitor of NF-kappa B, selectively on endothelium, and their wild-type littermates to define the role of endothelial-specific NF-kappa B in septic coagulation. In wild-type mice, lipopolysaccharide (LPS) challenge (5 mg/kg intraperitoneally) caused markedly increased plasma markers of coagulation, decreased plasma fibrinogen level, and widespread tissue fibrin deposition, which were abrogated by endothelial NF-kappa B blockade in transgenic mice. Endothelial NF-kappa B blockade inhibited tissue factor expression in endothelial cells, but not in leukocytes. Endothelial NF-kappa B blockade did not inhibit LPS-induced tissue factor expression in heart, kidney, and liver. Endothelial NF-kappa B blockade prevented LPS down-regulation of endothelial protein C receptor (EPCR) and thrombomodulin protein expressions, inhibited tissue tumor necrosis factor-alpha converting enzyme activity, reduced EPCR shedding, and restored plasma protein C level. Our data demonstrate that endothelial intrinsic NF-kappa B signaling plays a pivotal role in septic coagulation and suggests a link between endothelial-specific NF-kappa B activation and the impairment of the thrombomodulin-protein C-EPCR anticoagulation pathway. (Blood. 2009; 114: 2521-2529)