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

Authors

  • J. Sundaram,

    1. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX, USA
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  • S. Keshava,

    1. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX, USA
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  • R. Gopalakrishnan,

    1. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX, USA
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  • C. T. Esmon,

    1. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, OK, USA
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  • U. R. Pendurthi,

    1. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX, USA
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  • L. V. M. Rao

    Corresponding author
    1. Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX, USA
    • Correspondence: L. Vijaya Mohan Rao, Department of Cellular and Molecular Biology, Center for Biomedical Research, The University of Texas Health Science Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA.

      Tel.: +1 903 877 7332; fax: +1 903 877 7426.

      E-mail: Vijay.Rao@uthct.edu

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  • Manuscript handled by: W. Ruf
  • Final decision: P. H. Reitsma, 4 February 2014

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.

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