Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo

Abstract

Summary Background Recent studies have shown that factor VIIa binds to endothelial cell protein C receptor (EPCR), a cellular receptor for protein C and activated protein C. At present, the physiologic significance of FVIIa interaction with EPCR in vivo remains unclear. Objective: To investigate whether exogenously administered FVIIa, by binding to EPCR, induces a barrier protective effect in vivo. Methods Lipopolysaccharide (LPS)-induced vascular leakage in the lung and kidney, and vascular endothelial growth factor (VEGF)-induced vascular leakage in the skin, were used to evaluate the FVIIa-induced barrier protective effect. Wild-type, EPCR-deficient, EPCR-overexpressing and hemophilia A mice were used in the studies. Results Administration of FVIIa reduced LPS-induced vascular leakage in the lung and kidney; the FVIIa-induced barrier protective effect was attenuated in EPCR-deficient mice. The extent of VEGF-induced vascular leakage in the skin was highly dependent on EPCR expression levels. Therapeutic concentrations of FVIIa attenuated VEGF-induced vascular leakage in control mice but not in EPCR-deficient mice. Blockade of FVIIa binding to EPCR with a blocking mAb completely attenuated the FVIIa-induced barrier protective effect. Similarly, administration of protease-activated receptor 1 antagonist blocked the FVIIa-induced barrier protective effect. Hemophilic mice showed increased vascular permeability, and administration of therapeutic concentrations of FVIIa improved barrier integrity in these mice. Conclusions This is the first study to demonstrate that FVIIa binding to EPCR leads to a barrier protective effect in vivo. This finding may have clinical relevance, as it indicates additional advantages of using FVIIa in treating hemophilic patients.

Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

“…63 Additional studies revealed that EPCR-FVIIa activation of PAR1 leads to the barrier protective effect both in vitro and in vivo. 63,64 At present, it is unknown whether EPCR-FVIIa-PAR1-induced cytoprotection observed in our studies was mediated by the same mechanisms that had been proposed for EPCR-APC.…”

“…72 Our recent studies of VEGFinduced permeability in the skin further established the importance of EPCR in providing a barrier protective effect. 64 Our studies also showed that exogenous administration of FVIIa is as effective as APC in restoring the barrier integrity disrupted by vascular endothelial growth factor 64 or LPS administration (L.V.M., C.T.E. and U.R.P., unpublished data, January 2012).…”

“…The FVIIa-induced barrier protective effect in vivo is dependent on EPCR and involves PAR1 activation. 64 …”

Inactivation of Factor VIIa by Antithrombin In Vitro, Ex Vivo and In Vivo: Role of Tissue Factor and Endothelial Cell Protein C Receptor

“…The interaction between FVIIa and EPCR is capable of not only eliciting protease activated receptor-1 (PAR1)-mediated barrier protective signaling [22], [23], but also promotes internalization of the receptor–ligand complex [24]. At present, it is unknown whether FVIIa binding to EPCR influences AT inactivation of FVIIa.…”

Heterozygous congenital Factor VII deficiency with the 9729del4 mutation, associated with severe spontaneous intracranial bleeding in an adolescent male

“…EPCR is critical to maintain vascular barrier function [19] and FVIIa can mediate barrier protective effects via the EPCR-PAR1 signaling pathway [20, 21]. A decrease in FVIIa activity, as seen in the 9729del4 mutation, could therefore potentially diminish protective signaling via this pathway resulting in vascular instability.…”