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

• Published in: Journal of thrombosis and haemostasis 2014-05, Vol.12 (5), p.690-700
• Main Authors: Sundaram, J., Keshava, S., Gopalakrishnan, R., Esmon, C. T., Pendurthi, U. R., Rao, L. V. M.
• Format: Article
• Language: English
• Subjects: activated protein C receptor; Animals; Blood Coagulation Factors - metabolism; Capillary Permeability; Cells, Cultured; Endothelial Cells - cytology; factor VIIa; Factor VIIa - metabolism; Factor Xa - metabolism; Female; Genotype; hemophilia A; Hemophilia A - metabolism; Humans; Lipopolysaccharides - chemistry; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Permeability; Protein Binding; protein C; Protein C - metabolism; Receptors, Cell Surface - metabolism; Thrombin - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.12532

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.