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

Abstract

Generalized cellular ‘stress’ (i.e., oxidative, mitochondrial) within the syncytiotrophoblast (STB) layer of placenta is theorized to drive the pathogenesis of preeclampsia (PE), but the causes and consequences of this stress have yet to be clearly elucidated. Many hormones implicated in the disorder signal through the Gq pathway and have been associated with placental oxidative damage and maternal symptoms. Here, we provide novel evidence of elevated Gq stimulation (n=8-10 normalized area PLCB protein, control 1340±370, PE 3350±750, P=0.04) and an antioxidant response (n=8 normalized area SOD2 protein, control 3020±1160, PE 6700±1250, P=0.04) within STB cells of PE placenta. Thus, we hypothesized excess STB-specific Gq signaling would be sufficient to cause phenotypes of PE and that administration of a mitochondrial-targeted antioxidant (mitoquinone) would mitigate these effects. Activation of the Gq cascade 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 stimulation increased mean arterial pressure (n=6-8, CNO 115±2mmHg, saline 110±2mmHg, GD 13-16.5, P=0.04), exacerbated urine protein excretion (n=9-11 CNO 43±4mg/d, saline 28±3mg/day, P=0.001), and elevated circulating pro-inflammatory factors (MCP5, LIX, TIMP1, MIP3B, GCSF, IL12p40, MDC, P<0.05). Placental assessments revealed decreased labyrinth vascularization (n=10 CD31-positive area, Cre+ 19±1%, Cre– 24±1%, saline 23±1%, P<0.01 Cre+ vs. each), diminished spiral artery diameter (n=7-12 Cre+ 113±10μm, saline 149±12μm, P=0.03), and augmented oxidant defenses to mitochondrial-derived superoxide (n=7-9 normalized area SOD2 protein, Cre+ 18.2±3, saline 4.5±0.4, P=0.003; RNA sequencing enrichment of genes related to superoxide metabolic process, FDR=0.09). Remarkably, administration of mitoquinone in CNO-injected pregnancies reduced urine protein excretion (22±4mg/day, P=0.005), decreased circulating pro-inflammatory factors (LIX, IL12p40, MDC, P<0.05), attenuated plasma sFLT1 (P=0.048), and maintained placental vascularization (n=8 CD31-positive labyrinth, 23±1%, P=0.04; n=7 spiral artery diameter, 164±18 μm P=0.02). These data support a causative relationship between syncytiotrophoblast stress and the development of preeclampsia and identify elevated Gαq signaling as a contributing mechanism involving mitochondrial-derived reactive oxygen species. NIH: HL134850, HL084207, DK133121, HL150340; AHA: 826132, 18EIA33890055 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.