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

Summary Background Recent studies have shown that factor  VII a binds to endothelial cell protein C receptor ( EPCR ), a cellular receptor for protein C and activated protein C. At present, the physiologic significance of FVII a interaction with EPCR in vivo remains unclear. Objective To investigate whether exogenously administered FVII a, 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 FVII a‐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 mA b 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 FVII a binding to EPCR leads to a barrier protective effect in vivo . This finding may have clinical relevance, as it indicates additional advantages of using FVII a in treating hemophilic patients.