Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum

Abstract

Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q−/− model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q−/− male mice to model a preeclampsia-like pregnancy (“PE-like”), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q−/− model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond

“…C1q deficient mice have reduced litter size, suggesting a significant effect on fetal viability. This reduced fetal viability could be due to the placental insufficiency observed (71) or altered vascular function demonstrated in offspring of preeclamptic like pregnancies (72)(73)(74). In humans, another avenue of research associated with complement and recurrent pregnancy loss relates to development of anti-C1q antibodies.…”

Investigation of a Paternal-Mediated Preeclampsia-Like Pregnancy Phenotype Mouse Model

“…Blood Pressure: Volume-pressure recording by tail cuff method was utilized to measure blood pressure during mid (gestation day 9.5-11.5) and late pregnancy (gestation day 14.5-17.5) using the CODA-2 blood pressure monitoring system (Kent Scientific, Torrington, CT) (10,22). Mice were acclimated for 10-20 minutes per day for a minimum of two days before data collection.…”

“…Research in Dr. Powers' lab has extended this work by assessing vascular function during pregnancy and postpartum in C57 x C57 and C1q -/x C57 dams (22).…”

Complement in structure and immune homeostasis in placenta

“…Indeed, evidence shew that failure in complement-facilitated phagocytosis of debris may contribute to SLE as well as pathologic pregnancy 52,53 . C1q gene defect is a strong risk factor for SLE 54,55 , and C1q deficiency can also lead to pathological pregnancy like PE, and anti-C1q antibodies is associated with recurrent pregnancy loss (RPL) [56][57][58] . The level of C1q in the placenta of PE patients are significantly higher than those of normal pregnant women.…”

“…While too low C1q levels may impair the elimination of apoptotic cells and also subsequent immune homeostasis in placenta which threaten pregnancy. C1q deficiency can lead to pathological pregnancy like PE, and anti-C1q antibodies is associated with recurrent pregnancy loss (RPL) [56][57][58] . These evidences indicate that C1q play an important part in the maintenance of pregnancy.…”