Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gq signaling

Syncytiotrophoblast stress is theorized to drive development of preeclampsia, but its molecular causes and consequences remain largely undefined. Multiple hormones implicated in preeclampsia signal via the G alpha q cascade, leading to the hypothesis that excess G alpha q signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased G alpha q signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, G alpha q was activated in mouse placenta using Cre-lox and DREADD methodologies. Syncytiotrophoblast-restricted G alpha q activation caused hypertension, kidney damage, proteinuria, elevated circulating proinflammatory factors, decreased placental vascularization, diminished spiral artery diameter, and augmented responses to mitochondrial-derived superoxide. Administration of the mitochondrial-targeted antioxidant Mitoquinone attenuated maternal proteinuria, lowered circulating inflammatory and anti-angiogenic mediators, and maintained placental vascularization. These data demonstrate a causal relationship between syncytiotrophoblast stress and the development of preeclampsia and identify elevated G alpha q signaling and mitochondrial reactive oxygen species as a cause of this stress.