Preeclampsia Downregulates MicroRNAs in Fetal Endothelial Cells: Roles of miR-29a/c-3p in Endothelial Function

Zhou, Chi; Zou, Qingyun; Li, Hua; Wang, Ruifang; Liu, Aixia; Magness, Ronald R.; Zheng, Jing

doi:10.1210/jc.2017-00849

Cited by 50 publications

(86 citation statements)

References 49 publications

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“…Cell permeability was examined using an electric cell‐substrate impedance sensing system (ECIS Zθ; Applied Biophysics, Troy, NY, USA) as described previously (Zhou et al . ). Briefly, HUVECs were treated with vehicle, ssiRNA or GNA11 siRNA as described above.…”

Section: Methodsmentioning

confidence: 97%

“…HUVECs were isolated from umbilical cord veins of normal pregnancy using a collagenase enzyme protocol described previously (Jiang et al 2013a(Jiang et al , b, 2014Li et al 2015;Zhou et al 2017). After isolation, cells were cultured in endothelial culture medium (ECM) (catalog number 1001; Sciencell, Carlsbad, CA, USA) supplemented with 5% fetal bovine serum (FBS), 1% penicillin/streptomycin (p/s), 1% amphotericin B (AB) (catalog number 15290018; Thermo Fisher Scientific, Waltham, MA, USA) and 1% endothelial cell growth supplement (ECGS) under physiological chronic normoxia (PCN) (37°C, 5% CO 2 , 3% O 2 , ß92% N 2 ).…”

Section: Primary Huvecs and Culture Conditionsmentioning

confidence: 99%

“…; Zhou et al . ). Thus, a better understanding of the regulation of fetoplacental endothelial growth and function is a prerequisite for the design of therapeutic controls for fetoplacental vascular function.…”

Section: Introductionmentioning

confidence: 97%

“…In addition, impaired fetoplacental vascular growth and function are associated with several pregnancy complications, including pre-eclampsia and intrauterine growth restriction (Zygmunt et al 2003). These complications not only jeopardize maternal and fetal health, but also increase the risk of cardiovascular disease onset in adult offspring (Wang et al 2002;Powe et al 2011;Boeldt et al 2014;Brodowski et al 2017;Zhou et al 2017). Thus, a better understanding of the regulation of fetoplacental endothelial growth and function is a prerequisite for the design of therapeutic controls for fetoplacental vascular function.…”

Section: Introductionmentioning

confidence: 99%

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GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

Zou

Zhao

et al. 2018

The Journal of Physiology

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During pregnancy, fetoplacental angiogenesis is dramatically increased in association with rapidly elevated blood flow. Any disruption of fetoplacental angiogenesis may lead to pregnancy complications such as intrauterine growth restriction. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are crucial regulators of fetoplacental angiogenesis. G protein α subunits q (GNAq) and 11 (GNA11) are two members of the Gα subfamily involved in mediating vascular growth and basal blood pressure. However, little is known about the roles of GNA11 alone with respect to mediating the FGF2- and VEGFA-induced fetoplacental endothelial function. Using a cell model of human umbilical cord vein endothelial cells cultured under physiological chronic low O (3% O ), we showed that GNA11 small interfering RNA (siRNA) dramatically inhibited (P < 0.05) FGF2- and VEGFA-stimulated fetoplacental endothelial migration (by ∼36% and ∼50%, respectively) but not proliferation and permeability. GNA11 siRNA also elevated (P < 0.05) FGF2- and VEGFA-induced phosphorylation of phospholipase C-β3 (PLCβ3) at S537 in a time-dependent fashion but not mitogen-activated protein kinase 3/1 (ERK1/2) and v-akt murine thymoma viral oncogene homologue 1 (AKT1). These data suggest that GNA11 mediates FGF2- and VEGFA-stimulated fetoplacental endothelial cell migration partially via altering the activation of PLCβ3.

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Section: Methodsmentioning

confidence: 97%

Section: Primary Huvecs and Culture Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

Zou

Zhao

et al. 2018

The Journal of Physiology

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“…There were no studies where miR-193b differential expression was detected in blood samples. Overexpression of miR-193b-3p represses proliferation, invasion, migration and growth of cancer cells (Zhou et al, 2016). In experiments in vitro, upregulation of miR-193b-3p has been found to inhibit the migration and invasion of trophoblast cells by targeting TGF-β2 (transforming growth factor-β), which demonstrated significantly lower levels of mRNA and protein in PE placentas (Zhou et al, 2016).…”

Section: Mirnas In Studies With Mir-210mentioning

confidence: 99%

Publication-based analysis of miR-210 dependent biomarkers of pre-eclampsia

Tkachenko

Илларионов

Vashukova

et al. 2020

BioComm

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MicroRNAs (miRNAs) are potential biomarkers of most pregnancy complications. In recent years, miR-210 has been shown as one of the main biomarkers, detected at different stages of pregnancy and associated with various diseases, including pre-eclampsia (PE). However, miR-210 is not reported as a marker of PE in about half of the studies. We filtered available published RNA-seq data and miRNAs associated with PE, including or excluding miR-210, obtained from the PregMiR database. For further analysis we only considered miRNAs appearing in at least four different studies. We observed that miR-152, miR-1 and miR-193b were only detected in studies with a changed miR-210 level, whereas miR-27a, miR-29a, miR-130a and miR-519b were detected in studies without miRNA-210 differential expression. Common biomarkers of PE are miR-182, miR-126, miR-155, miR-181a, miR-18a, miR-195, miR-21, miR-223, miR-335, miR-517c, miR-518b, miR-518e and let-7f. Based on the obtained data and taking into account the direction of differential miRNA expression, it can be assumed that the most likely mechanisms of PE development in the early pregnancy stage are either upregulation of miR-210, miR-152, miR-518b and downregulation of miR-126; or upregulation of miR-126 and downregulation of miR-182 and miR-518b. Late stages of PE are determined by miR-210, miR-152, miR-518b, miR-21, miR-155, miR-181a, miR-182, miR-193b-3p, miR-517c, miR-518e (upregulation) and miR-126, miR-18a, miR-195, miR-223, let-7f (downregulation); or miR-27a, miR-29a, miR-130a and miR-519d, miR-517c, miR-518e miR-155, miR-126, miR-181a, miR-195 (upregulation) and miR-223, miR-18a, miR-182 (downregulation). The presented results allow speculation about the influence of certain miRNAs on PE development in the context of the presence or absence of miR-210 differential expression, but additional experimental studies are required to evaluate the findings.

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Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia

Mirzakhani,

Handy,

et al. 2023

Clinical & Translational Med

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BackgroundMicroRNAs (miRNAs) have been implicated in the pathobiology of preeclampsia, a common hypertensive disorder of pregnancy. In a nested matched case‐control cohort within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we previously identified peripheral blood mRNA signatures related to preeclampsia and vitamin D status (≤30 ng/mL) during gestation from 10 to 18 weeks, using differential expression analysis.MethodsUsing quantitative PCR arrays, we conducted profiling of circulating miRNAs at 10–18 weeks of gestation in the same VDAART cohort to identify differentially expressed (DE) miRNAs associated with preeclampsia and vitamin D status. For the validation of the expression of circulating miRNA signatures in the placenta, the HTR‐8/SVneo trophoblast cell line was used. Targets of circulating miRNA signatures in the preeclampsia mRNA signatures were identified by consensus ranking of miRNA‐target prediction scores from four sources. The connected component of target signatures was identified by mapping to the protein‐protein interaction (PPI) network and hub targets were determined. As experimental validation, we examined the gene and protein expression of IGF1R, one of the key hub genes, as a target of the DE miRNA, miR‐182‐5p, in response to a miR‐182‐5p mimic in HTR‐8/SVneo cells.ResultsPregnant women with preeclampsia had 16 circulating DE miRNAs relative to normal pregnancy controls that were also DE under vitamin D insufficiency (9/16 = 56% upregulated, FDR < .05). Thirteen miRNAs (13/16 = 81.3%) were detected in HTR‐8/SVneo cells. Overall, 16 DE miRNAs had 122 targets, of which 87 were unique. Network analysis demonstrated that the 32 targets of DE miRNA signatures created a connected subnetwork in the preeclampsia module with CXCL8, CXCL10, CD274, MMP9 and IGF1R having the highest connectivity and centrality degree. In an in vitro validation experiment, the introduction of an hsa‐miR‐182‐5p mimic resulted in significant reduction of its target IGF1R gene and protein expression within HTR‐8/SVneo cells.ConclusionsThe integration of the circulating DE miRNA and mRNA signatures associated preeclampsia added additional insights into the subclinical molecular signature of preeclampsia. Our systems and network biology approach revealed several biological pathways, including IGF‐1, that may play a role in the early pathophysiology of preeclampsia. These pathways and signatures also denote potential biomarkers for the early stages of preeclampsia and suggest possible preventive measures.

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Preeclampsia Downregulates MicroRNAs in Fetal Endothelial Cells: Roles of miR-29a/c-3p in Endothelial Function

Abstract: Preeclampsia-downregulated miR-29a/c-3p may impair fetal endothelial function by disturbing the FGF2-activated PI3K-AKT signaling pathway, hence inhibiting endothelial cell migration.

Cited by 50 publications

References 49 publications

GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

Publication-based analysis of miR-210 dependent biomarkers of pre-eclampsia

Integration of circulating microRNAs and transcriptome signatures identifies early‐pregnancy biomarkers of preeclampsia

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