Abstract 102: Mitoquinone Reduces Preeclamptic Phenotypes Associated With Syncytiotrophoblast-Specific Gq Signaling

Syncytiotrophoblast (STB) stress is theorized to drive the pathogenesis of preeclampsia (PE), and Gq-activating hormones implicated in PE have been associated with placenta oxidative damage, mitochondrial dysfunction, and maternal symptomology. As the causes and consequences of STB stress remain largely unknown, we used an in vivo model to determine whether excess STB-specific Gq signaling is sufficient to cause phenotypes of PE and if a mitochondrial-targeted antioxidant (mitoquinone) mitigates these effects. Activation of Gq signaling in STB cells was achieved by crossing dams harboring a cre-dependent Gq-coupled DREADD (hM3Dq) with Gcm1 -Cre +/- sires and injecting clozapine N-oxide (CNO) or saline mid-gestation (GD12.5-14.5) before tissue collection at GD14.5. Gq activation resulted in maternal proteinuria (n=9-11 CNO 43±4 vs saline 28±3mg/day; p=0.01), mild segmental congestion of glomerular capillaries, and elevated circulating IP-10 (p=0.03), MCP-5 (p=0.04), and IL-12p40 (p=0.01). hM3Dq stimulation reduced labyrinth vascularization (n=10 Cre + 19±1%, Cre - 24±1%, saline 23±1%; p<0.01 Cre + vs each), spiral artery diameter (n=7-11 Cre + 110±11μm, Cre - 135±9, saline 149±12 μm; p=0.03), placenta mass (n=10-13 Cre + 0.12±0.01, Cre - 0.14±0.01, saline 0.13±0.01g; p<0.01), and fetal mass (n=10-13 Cre + 0.23±0.03, Cre - 0.30±0.02, saline 0.29±0.02g; p<0.01). Preliminary data suggest a placental oxidative defense response to Gq induction based on increased protein levels of SOD2 and catalase, and decreased malondyaldehyde. Mitoquinone (5mg/kg) corrected maternal proteinuria (n=8 22±4mg/day, p<0.01), decreased circulating IL-12p40 (p=0.03), and protected both labyrinth vascularization (n=8 23±1%, p=0.05) and spiral artery diameter (n=8 164±18μm, p=0.02). These data indicate that elevated Gq signaling in the STB layer is sufficient to cause pathological features of PE, via a mechanism involving mitochondrial stress.