MicroRNA-376c Impairs Transforming Growth Factor-β and Nodal Signaling to Promote Trophoblast Cell Proliferation and Invasion

Fu, Guodong; Ye, Gang; Nadeem, Lubna; Ji, Lei; Manchanda, Tanita; Wang, Yongqing; Zhao, Yangyu; Qiao, Jie; Wang, Yanling; Lye, Stephen J.; Yang, Burton B.; Peng, Chun

doi:10.1161/hypertensionaha.111.203489

Cited by 156 publications

(148 citation statements)

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“…PET is a major disorder of pregnancy characterized by an increased maternal inflammatory response and vascular dysfunction, 14 affecting placentation, trophoblast proliferation, invasion, 15 and apoptosis. The current study demonstrated that NHP women and women with GVC displayed similar levels of circulating MVs, which is in accordance with our previous report 10 and other studies.…”

Section: Discussionmentioning

confidence: 99%

Microvesicles of Women With Gestational Hypertension and Preeclampsia Affect Human Trophoblast Fate and Endothelial Function

et al. 2013

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Microvesicles shedding from cell membrane affect inflammation, apoptosis, and angiogenesis. We hypothesize that microvesicles of women with gestational vascular complications reflect pathophysiological state of the patients and affect their endothelial and trophoblast cell function. Microvesicles of healthy pregnant women, women with gestational hypertension, mild, or severe preeclampsia/toxemia, were characterized, and their effects on early-stage or term trophoblasts and endothelial cells were evaluated using apoptosis, migration, and tube formation assays. Patient subgroups differed significantly only in proteinuria levels, therefore their microvesicles were assessed as 1 group, demonstrating higher levels of inflammatory and angiogenic proteins compared with those of healthy pregnant women. In endothelial cells, microvesicles of healthy pregnant women reduced caspase 3/7 activity, increased migration, and induced tube formation. These processes were suppressed by microvesicles of women with gestational vascular complications. In early-stage trophoblasts, microvesicles of healthy pregnant women decreased apoptosis compared with untreated cells (6±5% versus 13.8±5.8%; P <0.001) and caspase 3/7 activity and induced higher migration (39.7±10.1 versus 20.3±8.3 mm 2 ; P <0.001). This effect was mediated through extracellular signal-regulated kinase pathway. Conversely, microvesicles of women with gestational vascular complications increased term trophoblast apoptosis compared with cells exposed to microvesicles of healthy pregnant women (15.1±3.3% versus 6.5±2.1%; P <0.001) and inhibited early-stage trophoblasts migration (21.4±18.5 versus 39.7±10.1 mm 2 ; P <0.001). In conclusion, microvesicle content and effects on endothelial and trophoblast cells vary according to the physiological/pathological state of a pregnant woman. Microvesicles seem to play a pivotal role in the course of pregnancy, which could potentially result in gestational vascular complications.

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Section: Discussionmentioning

confidence: 99%

Microvesicles of Women With Gestational Hypertension and Preeclampsia Affect Human Trophoblast Fate and Endothelial Function

et al. 2013

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“…These studies were carried out in The People's Republic of China [33e35, 37,40,42,43,45,50,52e58,63,64,67,69,72e74], the USA [32,46e48,51,54,61,70,71], South Korea [49], Canada [50,60], Japan [62], Turkey [65], Chile [66], Germany [68], Hungary [59], Switzerland [36], Norway [38], Italy [39], Spain [41], and the Czech Republic [44] (see Table 1 for details).…”

Section: Resultsmentioning

confidence: 99%

“…Fu et al [50] found that miR-376c is downregulated in preeclamptic placenta samples and that this targets ALK7 and ALK5, which are molecules important to the Nodal signaling pathway. The study also confirmed that Nodal and ALK7 levels are upregulated in preeclamptic placenta samples [50]. Therefore, downregulation of miR-376c in the preeclamptic placenta results in higher ALK7 expression and this then results in the enhancement of Nodal signaling (Fig.…”

Section: The Roles Of Mirnas In Trophoblast Proliferation Survival Amentioning

confidence: 99%

The role of microRNAs in the proliferation, differentiation, invasion, and apoptosis of trophoblasts during the occurrence of preeclampsia—A systematic review

Harapan

Andalas

2015

Tzu Chi Medical Journal

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Keywords: microRNA miRNA Preeclampsia pathogenesis Trophoblast apoptosis Trophoblast invasiveness a b s t r a c t Objectives: Dysregulation of trophoblast invasion into the decidual stroma and spiral arteries during early gestation is one of the major factors associated with the pathogenesis of preeclampsia. Therefore, the objective of this study was to evaluate, based on recent studies, the role of microRNAs (miRNAs) in trophoblast proliferation, differentiation, invasion, and apoptosis during the early gestation of preeclamptic pregnancies. Materials and methods: This systematic review included articles between 2007 and 2015 that were obtained from the MEDLINE database. The articles were identified by searching using a combination of Medical Subject Headings (MeSH terms), namely "preeclampsia", "pre-eclampsia", "miRNA", and "microRNA". All sources of miRNAs, all types of preeclampsia, and all techniques used when measuring miRNAs were included in the reviewed papers. Results: Confirmed upregulation of miR-125b-1-3p, miR-20a, miR-29b, miR-181a, miR-16, miR-210, and miR-155 and confirmed downregulation of miR-17, miR-19b1, miR-195, miR-378a-5p, miR-376c, and miR-675 were identified as involved in repressing the proliferation, differentiation, and invasion of trophoblast cells. In addition, upregulation of miR-29b and downregulation of miR-378a-5p and miR376c were found to be associated with increased trophoblast cell apoptosis. Conclusion: Overall, miRNAs have been confirmed to be involved in the shallow invasion by trophoblasts into the spiral arteries and decidual stroma during early gestation and these miRNAs are possible promising biomarkers that may help to predict preeclampsia in the future.

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“…To establish miR-376c as a predictive or diagnostic biomarker of preeclampsia, the study by Fu and colleagues 7 requires confirmation in independent and larger cohorts. Already at this stage, however, it provides a better understanding of the processes leading to impaired trophoblast invasion…”

Section: April 2013mentioning

confidence: 99%

“…Nevertheless, the available studies confirm dysregulation of miRNAs that play a role in the regulation of trophoblast cell invasion, such as miR-195 4 and miR-29b, 5 and mitochondrial function such as miR-210. 6 In this issue of Hypertension, 7 Fu and colleagues assess, in detail, one particular miRNA, miR-376c, and its expression and function in normal pregnancy and in preecampsia using a range of cellular assays, molecular manipulations, and patient materials. miR376c is expressed within a region of imprinted DNA on human chromosome 14, a region rich in noncoding RNA species, including an abundance of distinct miRNAs (http://www.ensembl.…”

mentioning

confidence: 99%

Is MicroRNA-376c a Biomarker or Mediator of Preeclampsia?

Baker

Delles

2013

Hypertension

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MicroRNA-376c Impairs Transforming Growth Factor-β and Nodal Signaling to Promote Trophoblast Cell Proliferation and Invasion

Abstract: The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl

Cited by 156 publications

References 49 publications

Microvesicles of Women With Gestational Hypertension and Preeclampsia Affect Human Trophoblast Fate and Endothelial Function

Microvesicles of Women With Gestational Hypertension and Preeclampsia Affect Human Trophoblast Fate and Endothelial Function

The role of microRNAs in the proliferation, differentiation, invasion, and apoptosis of trophoblasts during the occurrence of preeclampsia—A systematic review

Is MicroRNA-376c a Biomarker or Mediator of Preeclampsia?

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