Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities
Angelina J. Lay, … , Elliot D. Rosen, Francis J. Castellino
Angelina J. Lay, … , Elliot D. Rosen, Francis J. Castellino
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1552-1561. https://doi.org/10.1172/JCI24030.
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Research Article Hematology

Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities

Abstract

Anticoagulant protein C (PC) is important not only for maintenance of normal hemostasis, but also for regulating the host immune response during inflammation. Because mice with a designed total genetic deficiency in PC (PC–/– mice) die soon after birth, attempts to dissect PC function in various coagulation/inflammation-based pathologies through use of mice with less than 50% of normal PC levels have not been successful to date. In the current investigation, we have used a novel transgenic strategy to generate different mouse models expressing 1–18% of normal PC levels. In contrast to PC–/– mice, mice with only partial PC deficiency survived beyond birth and also developed thrombosis and inflammation. The onset and severity of these phenotypes vary significantly and are strongly dependent on plasma PC levels. Our findings additionally provide the first evidence that maternal PC is vital for sustaining pregnancy beyond 7.5 days postcoitum, likely by regulating the balance of coagulation and inflammation during trophoblast invasion. These low PC–expressing transgenic mouse lines provide novel animal models that can be used to elucidate the importance of PC in maintenance of the organism and in disease.

Authors

Angelina J. Lay, Zhong Liang, Elliot D. Rosen, Francis J. Castellino

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Figure 2

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PC levels correlate with poor survival in unchallenged low-PC mice. (A) ...
PC levels correlate with poor survival in unchallenged low-PC mice. (A) Plasma PC levels were measured in mice derived from WT and the various low-PC transgenic lines using ELISA methodology. In PC–/–(PCTg535), PC–/–(PCTg4), PC–/–(PCTg785), and PC–/–(PCTg527) mice, the levels of plasma PC represents less than 1%, 1%, 3%, and 18% of age- and gender-matched WT plasma respectively. (B) Survival of mixed-gender progenies derived from various PC transgenic lines. The values in parentheses indicate the PC levels in the corresponding strains as percent of WT values. PC–/–(PCTg535) offspring (n = 46) had the poorest survival and the lowest PC levels compared with progenies from PC–/–(PCTg527) (n = 49), PC–/–(PCTg785) (n = 144), or PC–/–(PCTg4) (n = 63) strains. The disease onset and death in PC–/–(PCTg535) littermates occurred at a young age (<1 month). In contrast, offspring from PC–/–(PCTg4) and PC–/–(PCTg785) mice had late-onset thrombotic phenotypes and accordingly longer survival. Progenies from PC–/–(PCTg527) mice lacked spontaneous phenotypes and developed normally.