Variations of MicroRNAs in Human Placentas and Plasma From Preeclamptic Pregnancy

Abstract

Abstract-Preeclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. The differential expression of several microRNAs (miRNAs) has been found in preeclamptic placentas. However, great conflict exists regarding this aspect, and detailed examinations have largely been lacking of miRNA profiles in different parts of the placenta and in maternal plasma of women with this disorder. In this study, a total of 9 downregulated miRNAs (miR-195, miR-223, miR-218, miR-17, miR-18a, miR-19b1, miR-92a1, miR-379, and miR-411) and 7 upregulated miRNAs (miR-210, miR-30a-3p, miR-518b, miR-524, miR-17-3p, miR-151, and miR-193b) were identified in severe preeclampsia (sPE) placentas when compared with normal pregnant controls. In addition, sampling position in the chorionic or basal plate of placenta led to evident variations in differential miRNAs of sPE placentas. In a prospective pregnant cohort, we found that the circulating levels of 3 members of miR-17-92 cluster (ie, miR-18a, miR-19b1, and miR-92a1) were significantly lower, whereas that of miR-210 was higher in sPE patients than those in normal controls at gestational weeks 15 to 18 and at term. The results of in situ hybridization revealed the localization of miR-18a, miR-92a1, and miR-210 in various subtypes of placental trophoblasts and endothelial cells. In human trophoblast cell line, HTR8/SVneo cells, miR-18a could promote trophoblast cell invasion via targeting and suppressing Smad2 expression. This study provides fundamental evidences for exploring the roles of miRNAs in the pathogenesis of preeclampsia. Variations of MicroRNAs in Human Placentas and Plasma From Preeclamptic Pregnancy Xu et al Differential miRNAs in Preeclampsia 1277modulating effect of miR-18a. The data provide important evidences for exploring the pathogenesis of the disease from a noncoding RNA viewpoint. Materials and MethodsAll the details of the materials and methods are provided in the online-only Data Supplement. Study SubjectsIn this study, the collection of human placenta tissues and plasma specimens was performed with the permission of the local ethical committee in the Institute of Zoology, Chinese Academy of Sciences, and informed consent was obtained from all patients enrolled in this study. Placentas and maternal blood samples from normal pregnant and preeclamptic women were obtained from pregnant women who underwent perinatal care in Peking University Third Hospital from August 2010 to October 2012. Totally 20 severe preeclamptic patients who delivered at 35th to 39th weeks and 33 normal pregnant women who delivered at 37th to 39th weeks were enrolled in this study. Their placentas at deliveries and plasma samples at gestational weeks 15 to 18 and weeks 35 to 38 were used. The clinical characteristics of these women are summarized in Table 1. miRNA Microarray AnalysisLarge-scale profiling of miRNA expression was achieved by mammalian miRNA chip array (V2.0, Capitalbio, Beijing, China), which stems from the miRbase release 8.2 (Wellcome Trust Genome Camp...

Testosterone Represses Estrogen Signaling by Upregulating miR-22

“…A great number of differentially expressed miRNAs have been identified in preeclamptic placentas, [15][16][17] and some of these differentially expressed miRNAs were demonstrated to participate in the regulation of various placental cell events and functions. [18][19][20] On the basis of these data, we speculate that the abnormally elevated androgen in PE patients may upregulate miR-22 expression in placental trophoblasts, which may target and repress ERα and aromatase and, accordingly, exacerbate the imbalanced production of androgen and estrogen in patients.To address this assumption, we examined the differential production of miR-22, 17β-HSD3, and aromatase in severe PE placentas. The effects of testosterone on miR-22, aromatase, and ERα expression, as well as estradiol production, were explored in the human trophoblastic cell line JEG-3.…”

MicroRNAs, immune cells and pregnancy

“…These include fetal weight restriction and low fetal birth weight (intrauterine growth retardation or IUGR), [81][82][83][84] toxin exposures such as environmental toxins, 85,86 cancer (hepatocellular carcinoma), 87 diabetes mellitus 88 and, the most heavily studied, human pre-eclampsia. 79,[89][90][91][92][93][94][95][96] Many of the pre-eclampsia studies have investigated miRNA expression using high throughput microarray, and qPCR (primarily in order to validate specific microarray findings). Previous studies have established that oxygen tension is implicated in placental development in humans and mice.…”

MicroRNA-210 Contributes to Preeclampsia by Downregulating Potassium Channel Modulatory Factor 1

“…for preeclampsia. 23,25 Despite these findings, the details of the role played by miR-210 in preeclampsia development remain largely unknown. …”

“…21,22,25 Until now, functional studies on miR-210 have mainly focused on its role in cancer. The reasons that miR-210 attracted our attention in the study of placenta development were as follows: (1) In our previous study, we found that the levels of miR-210 increased in the plasma of preeclamptic individuals early in gestation (15-18 weeks), 25 indicating its possible participation in the cause of preeclampsia at early gestation. (2) Target prediction results show that KCMF1 is one of the possible targets of miR-210, and the predicted binding site in the 3′-UTR of KCMF1 mRNA is evolutionarily conserved from amphibians to humans.…”