Complement activation in maternal and placental pathology of preeclampsia

Abstract

Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms linked to varying placental and maternal pathologies. While complement system dysregulation has been implicated in the pathogenesis of preeclampsia, its causal relationship and molecular mechanisms remain unclear. In mice, complement receptor 1-related protein y (Crry) functions as a critical complement regulator at the fetal-maternal interface, essential for early embryonic survival. Complete Crry deficiency is embryonically lethal, complicating in vivo studies of complement activation in pregnancy. Using an alternative strategy, we developed a placenta-specific, doxycycline-inducible shRNA mouse model utilizing Cyp19-driven Cre recombinase and a Tet-On system to downregulate Crry in a dose-dependent manner 9.5 days post coitus, effectively restricting complement activation to the placenta. Using this model, we demonstrate that early gestation but sustained placental complement activation impairs maternal heart and liver adaptation, reduces placental efficiency, and causes fetal growth restriction, mimicking early-onset preeclampsia. Conversely, delayed complement activation induces a phenotype more consistent with late-onset preeclampsia features without placental pathology. In early-onset preeclampsia-like phenotype, the fetal growth restriction is accompanied by placental glycogen storage deficiency, and impaired hormonal function. Maternal glucose metabolism is not affected but compensatory adaptations in lipid metabolism occur although insufficient to offset fetal growth restriction. This novel model reveals that the timing of placental complement activation dictates the spectrum of preeclampsia-like pathology, providing mechanistic insights into the pathophysiology of preeclampsia.