Mice with a Severe Deficiency of the Endothelial Protein C Receptor Gene Develop, Survive, and Reproduce Normally, and Do not Present with Enhanced Arterial Thrombosis after Challenge^[*]

Summary

The endothelial cell Protein C receptor (EPCR) functions to enhance activation of anticoagulant Protein C (PC) by the thrombin/ thrombomodulin (Tm) complex on the surface of the endothelium. This overall system functions in anticoagulation, profibrinolytic, and antiinflammatory responses. Mice with a severe targeted deficiency of this receptor have been generated by integration of exogenous DNA elements into the 5’-untranslated region of the EPCR gene. Despite the retention of the entire endogenous EPCR coding sequence in the altered EPCR gene locus, only very low EPCR message contents were detected in mice by quantitative RT-PCR during embryogenesis and up to at least early adulthood. Immunohistochemical analysis of various regions of the arterial tree of mice up to 4 months of age, employing an anti-murine EPCR antibody, confirmed that undetectable levels of this protein were present in arterial regions during these periods. Despite this, these mice are not more prone to arterial thrombosis after challenge in a FeCl3 carotid artery thrombosis model. Small amounts (<10% of wild-type) of this protein were found in other tissues. Matings of mice homozygous for this deficiency led to normal births and survival of the offspring, in contrast to results by others demonstrating early embryonic lethality of a total EPCR deficiency. These data further show that minimal levels of EPCR are able to support male and female virility, as well as embryonic development, birth, and survival to adulthood.

Keywords

EPCR - gene deficiency - embryogenesis - anticoagulation - reproduction

^* This work was supported by grants HL-19982 (to F. J. C.), HL-65241 (to E. D. R./F. J. C.) and HL60081 (to E. D. R.) from the National Institutes of Health, and the Kleiderer-Pezold endowed chair (to F. J. C.).

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