The Effects Of Potent Antioxidant MitoQ On The Development And Function Of Placenta Through Diminishing Mitochondrial Reactive Oxygen Species

Preeclampsia?PE?has long been attributed to excessive oxidative stress?OS?in placenta.However,clinical trials suggest that moderate antioxidants fail to prevent PE.Given that mitochondria are the major source and target of reactive oxygen species?ROS?,potent mitochondria-targeting antioxidant MitoQ might be eligible for PE prevention.In this study,placental OS were determined by 4HNE staining.Isolated placental mitochondria were subjected to transmission electron microscopy and enzyme activity of superoxide dismutase?SOD?and glutathione peroxidase?GPx?.MitoQ was orally administered to RUPP or sham mice during early or late gestation respectively.Blood pressure?BP?,urine protein placental weight,fetal birth weight,the sizes of labyrinth and blood sinus were then measured.HTR8-S/Vneo trophoblast cells were treated with various dosages of H₂O₂ and then cell viability was measured.The impact of OS on trophoblast invasion and migration were assessed by transwell and wound-healing assays respectively,and further validated by applying additional antioxidants.Whole genome RNA-sequencing was performed to investigate the pathways and genes be involved in trophoblast function regulation by OS.Human PE placentas and mouse RUPP placenta demonstrated significantly higher OS,which is in line with increased mitochondrial damage and compromised activities of SOD and GPx.MitoQ administration during late gestation alleviated RUPP-induced PE phenotype,while early-pregnancy MitoQ treatment exacerbated BP,fetal growth restriction and proteinuria.Moreover,the ratio of labyrinth/spongiotrophoblast and area of the blood sinuses in the labyrinth was greatly reduced by early-pregnancy MitoQ administration.1?M H₂O₂treatment significantly improved not only viability,but also invasion and migration in HTR8-S/Vneo cells,and such improvement was abolished by additional MitoQ or MitoTempo.RNAseq revealed that low OS has profound regulatory effects on trophoblastic gene expression,including miR-29b-3p,which regulates expression of 5 genes that involved in cell viability and mobility,along with 59 cirRNAs.Our findings suggested that low-level OS is required for trophoblast functions,use of potent antioxidant treatments during early pregnancy is detrimental for placentation and consequent in increased risks of PE,therefore,antioxidant therapy for pregnant women should be thoroughly considered.