Abstract
Preeclampsia is associated with first trimester placental dysfunction. miR-210, a small non-coding RNA, is increased in the preeclamptic placenta. The effects of elevated miR-210 on placental function remain unclear. The objectives of this study were to identify targets of miR-210 in first trimester primary extravillous trophoblasts (EVTs) and to investigate functional pathways altered by elevated placental miR-210 during early pregnancy. EVTs isolated from first trimester placentas were exposed to cobalt chloride (CoCl2), a HIF-1α stabilizer and hypoxia mimetic, and miR-210 expression by qPCR, HIF1α protein levels by western blot and cell invasion were assessed. A custom TruSeq RNA array, including all known/predicted miR-210 targets, was run using miR-210 and miR-negative control transfected EVTs. Mitochondrial function was assessed by high resolution respirometry in transfected EVTs. EVTs exposed to CoCl2 showed a dose and time-dependent increase in miR-210 and HIF1α and reductions in cell invasion. The TruSeq array identified 49 altered genes in miR-210 transfected EVTs with 27 genes repressed and 22 enhanced. Three of the top six significantly repressed genes, NDUFA4, SDHD, and ISCU, are associated with mitochondrial function. miR-210 transfected EVTs had decreased maximal, complex II and complex I+II mitochondrial respiration. This study suggests that miR-210 alters first trimester trophoblast function. miR-210 overexpression alters EVT mitochondrial function in early pregnancy. Mitochondrial dysfunction may lead to increased reactive oxygen species, trophoblast cell damage and likely contributes to the pathogenesis of preeclampsia.
Highlights
Preeclampsia (PE), a hypertensive disorder of pregnancy, affects 5–8% of pregnancies making it one of the world’s leading causes of maternal and fetal morbidity and mortality United States Department of Health and Human Services. (1991)
This study provides evidence that (1) elevated miR-210 expression has the ability to alter extravillous trophoblasts (EVTs) gene transcription in the first trimester of pregnancy, a time that is critical to normal placentation and fetal growth and (2) miR-210 plays a critical role in EVT mitochondrial function in the first trimester of pregnancy suggesting that alterations in miR-210 expression contribute to adverse obstetrical outcomes, especially PE
We have shown that overexpression of miR-210 in first trimester EVTs has the ability to repress or activate many genes across a wide range of biological functions with the most significant gene alterations being associated with mitochondrial function
Summary
PE is a disorder characterized clinically by the presence of maternal hypertension (greater than 140/90), proteinuria and edema after 20 weeks. The spectrum of symptoms associated with PE has resulted in the theory that there are two forms of PE, early- (before 34 weeks gestation) and late-onset PE with earlyonset PE correlating to more severe clinical manifestations of the disorder (Redman, 2017). Early-onset/severe PE is associated with higher rates of intrauterine growth restriction, preterm birth, and perinatal death indicating that placental dysfunction could be a major contributor to the development of PE. The hypoxic placenta stimulates the release of factors resulting in systemic maternal endothelial dysfunction and the clinical syndrome of PE (Maynard et al, 2003; Levine et al, 2004, 2006)
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