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.
View: Text | PDF
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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Gross phenotypes of the low-PC transgenic mice. (A and B) Early onset of...
Gross phenotypes of the low-PC transgenic mice. (A and B) Early onset of severe hemorrhage in the tails and legs of PC–/–(PCTg535) littermates. (C–G) Late onset of thromboembolic phenotypes in PC–/–(PCTg785) and PC–/–(PCTg4) offspring characterized by hemorrhagic skin lesions affecting various parts of the body (C: tail; D and E: paws; F: ear; G: face). (H and I) Specimens collected from PC–/–(PCTg785) mice euthanized due to illness. Multiple focal hemorrhagic lesions in the lung (H) and muscle (I) of the legs. (J) Severe necrosis of regions of the liver. (K) Tail bleeding times were measured in PC–/–(PCTg785) mice of various ages. The data are expressed as the fraction still bleeding as a function of time. No statistical differences were found in bleeding times between 8- and 12-week-old WT mice. In contrast, low-PC mice at 8 weeks showed significantly shorter bleeding times compared with WT mice, while the 12-week-old low-PC mice had significantly prolonged bleeding times compared with 8-week-old low-PC or WT mice.