Placental Expression of miR-517a/b and miR-517c Contributes to Trophoblast Dysfunction and Preeclampsia

Abstract

Preeclampsia is a pregnancy specific hypertensive disease that confers significant maternal and fetal risks. While the exact pathophysiology of preeclampsia is unknown, it is widely accepted that placental dysfunction is mechanistically involved. Recent studies reported aberrant expression of placenta-specific microRNAs (miRNAs) in preeclampsia including miR-517a/b and miR-517c. Using placental biopsies from a preeclampsia case-control study, we found increased expression of miR-517a/b in term and preterm preeclampsia vs controls, while, miR-517c was increased only in preterm preeclampsia vs controls. To determine if miR-517a/b and miR-517c are regulated by hypoxia, we treated first trimester primary extravillous trophoblast cells (EVTs) with a hypoxia mimetic and found both were induced. To test for a mechanistic role in placental function, we overexpressed miR-517a/b or miR-517c in EVTs which resulted in decreased trophoblast invasion. Additionally, we found that miR-517a/b and miR-517c overexpression increased expression of the anti-angiogenic protein, sFLT1. The regulation of sFLT1 is mostly unknown, however, TNFSF15, a cytokine involved in FLT1 splicing, was also increased by miR-517a/b and miR-517c in EVTs. In summary, we demonstrate that miR-517a/b and miR-517c contribute to the development of preeclampsia and suggest that these miRNAs play a critical role in regulating trophoblast and placental function.

MicroRNAs in placental health and disease

“…83 In addition to miR-210, differential expression of C19MC miRNA members has been reported, 131,139,140 including increased expression of C19MC miRNA members in extravillous trophoblasts from women with preeclampsia. Notably, preeclampsia is associated with reduced invasion of extravillous trophoblasts in vitro, 141 and this observation is consistent with the recent finding of reduced migration of human extravillous trophoblast cell line by over-expression of C19MC miRNAs. 90 Aberrant C19MC miRNA expression patterns have also been observed in placentas from pregnancies complicated by fetal growth restriction (FGR).…”

MiR‐30a attenuates immunosuppressive functions of IL‐1β‐elicited mesenchymal stem cells via targeting TAB3

“…The influence of MSCs on the innate and adaptive immune systems has been reported by several studies [9][10][11][12]. Our previous studies also showed that MSCs inhibited the inflammatory response in LPS-stimulated macrophages [20]. The abnormal activity of macrophages in the maternal-fetal interface was found to be related to the pathogenesis of PE [38].…”

“…MSCs and maternal plasma from PE patients [20][21][22][23][24]. Our previous studies found that miR-16 and miR-494 could inhibit the proliferation and migration of MSCs from severe PE patients [25,26] and that miR-181a could directly control the immunosuppressive function of MSCs [9].…”

Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes

“…Placental miRNAs appear to regulate both trophoblast cell migration and maternal immune response[67], which may occur in a sex-dependent fashion. For instance, miR-517b, which was associated with GDM among pregnancies with male fetuses only, regulates expression of TNFS15[68], a pro-inflammatory, anti-angiogenic cytokine, which may reflect a sex-specific placental response to the maternal immune system. In line with recent National Institutes of Health statements highlighting the growing awareness of differences in response to metabolic stressors by sex at all ages[69], future studies investigating fetal–sex-specific effects of miRNAs in pregnancy are warranted.…”