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Mitochondrial-targeted antioxidant attenuates preeclampsia-like phenotypes induced by syncytiotrophoblast-specific Gαq signaling. Sci Adv 2023 Dec;9(48):eadg8118

Date

12/01/2023

Pubmed ID

38039359

Pubmed Central ID

PMC10691776

DOI

10.1126/sciadv.adg8118

Scopus ID

2-s2.0-85178323055 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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 Gαq cascade, leading to the hypothesis that excess Gαq signaling within the syncytiotrophoblast may contribute. First, we present data supporting increased Gαq signaling and antioxidant responses within villous and syncytiotrophoblast samples of human preeclamptic placenta. Second, Gαq was activated in mouse placenta using Cre-lox and DREADD methodologies. Syncytiotrophoblast-restricted Gαq 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 Gαq signaling and mitochondrial reactive oxygen species as a cause of this stress.

Author List

Opichka MA, Livergood MC, Balapattabi K, Ritter ML, Brozoski DT, Wackman KK, Lu KT, Kozak KN, Wells C, Fogo AB, Gibson-Corley KN, Kwitek AE, Sigmund CD, McIntosh JJ, Grobe JL

Authors

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Anne E. Kwitek PhD Professor in the Physiology department at Medical College of Wisconsin
Jennifer Jury Mcintosh DO Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antioxidants
Female
GTP-Binding Proteins
Humans
Mice
Placenta
Pre-Eclampsia
Pregnancy
Proteinuria
Trophoblasts