Factor VIIa binding to endothelial cell protein C receptor: differences between mouse and human systems

Area of Science:

• * Biochemistry and Molecular Biology
• * Vascular Biology and Thrombosis

Background:

• * In vitro studies suggest factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR).
• * In vivo evidence of FVIIa binding EPCR alongside protein C is lacking.
• * Investigating FVIIa and EPCR interactions in vivo is crucial.

Purpose of the Study:

• * To investigate the in vivo and in vitro interactions of murine and human FVIIa with murine EPCR.
• * To determine if FVIIa binds EPCR on vascular endothelium in the presence of protein C.
• * To assess the influence of magnesium ions on FVIIa-EPCR binding.

Main Methods:

• * Measurement of endogenous plasma FVII levels in genetically modified mice.
• * In vivo immunohistochemistry to detect FVIIa binding to murine endothelium.
• * In vitro surface plasmon resonance and endothelial cell binding assays.

Main Results:

• * Murine FVIIa exhibits negligible binding to murine EPCR in vitro.
• * Human FVIIa binds efficiently to both murine and human EPCR, enhanced by Mg2+.
• * Human FVIIa, but not murine FVIIa, binds to murine endothelium in an EPCR-dependent manner in vivo.

Conclusions:

• * Murine FVIIa demonstrates poor interaction with EPCR, unlike human FVIIa.
• * Human FVIIa efficiently binds EPCR, suggesting its utility in preclinical models.
• * Consideration of human FVIIa in mouse models is recommended for studying FVIIa-EPCR interactions.