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Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells.

ABSTRACT: During the pregnancy associated syndrome preeclampsia (PE), there is increased release of placental syncytiotrophoblast extracellular vesicles (STBEVs) and free foetal haemoglobin (HbF) into the maternal circulation. In the present study we investigated the uptake of normal and PE STBEVs by primary human coronary artery endothelial cells (HCAEC) and the effects of free HbF on this uptake. Our results show internalization of STBEVs into primary HCAEC, and transfer of placenta specific miRNAs from STBEVs into the endoplasmic reticulum and mitochondria of these recipient cells. Further, the transferred miRNAs were functional, causing a down regulation of specific target genes, including the PE associated gene fms related tyrosine kinase 1 (FLT1). When co-treating normal STBEVs with HbF, the miRNA deposition is altered from the mitochondria to the ER and the cell membrane becomes ruffled, as was also seen with PE STBEVs. These findings suggest that STBEVs may cause endothelial damage and contribute to the endothelial dysfunction typical for PE. The miRNA mediated effects on gene expression may contribute to the oxidative and endoplasmic reticulum stress described in PE, as well as endothelial reprogramming that may underlay the increased risk of cardiovascular disease reported for women with PE later in life.

SUBMITTER: Cronqvist T

PROVIDER: S-EPMC5496854 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells.

Cronqvist Tina T Tannetta Dionne D Mörgelin Matthias M Belting Mattias M Sargent Ian I Familari Mary M Hansson Stefan R SR

Scientific reports 20170704 1

During the pregnancy associated syndrome preeclampsia (PE), there is increased release of placental syncytiotrophoblast extracellular vesicles (STBEVs) and free foetal haemoglobin (HbF) into the maternal circulation. In the present study we investigated the uptake of normal and PE STBEVs by primary human coronary artery endothelial cells (HCAEC) and the effects of free HbF on this uptake. Our results show internalization of STBEVs into primary HCAEC, and transfer of placenta specific miRNAs from ...[more]

PMID: 28676635

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Project description:Preeclampsia (PE), defined as new-onset hypertension and multi-organ systemic complication during pregnancy, is the leading cause of maternal and neonatal mortality and morbidity. With extracellular vesicles research progresses, current data refers to the possibility that ferroptosis may play a role in exosomal effects. Evidence has suggested that ferroptosis may contribute to the pathogenesis of preeclampsia by bioinformatics analyses. The purpose of the current study is to identify the potential ferroptosis-related genes in syncytiotrophoblast-derived extracellular vesicles (STB-EVs) of preeclampsia using bioinformatics analyses. Clinical characteristics and gene expression data of all samples were obtained from the NCBI GEO database. The differentially expressed mRNAs (DE-mRNAs) in STB-EVs of preeclampsia were screened and then were intersected with ferroptosis genes. Functional and pathway enrichment analyses of ferroptosis-related DE-mRNAs in STB-EVs were performed. Ferroptosis-related hub genes in STB-EVs were identified by Cytoscape plugin CytoHubba with a Degree algorithm using a protein-protein interaction network built constructed from the STRING database. The predictive performance of ferroptosis-related hub genes was determined by a univariate analysis of receiver operating characteristic (ROC). The miRNA-hub gene regulatory network was constructed using the miRwalk database. A total of 1976 DE-mRNAs in STB-EVs were identified and the most enriched item identified by gene set enrichment analysis was signaling by G Protein-Coupled Receptors (normalized enrichment score = 1.238). These DE-mRNAs obtained 26 ferroptosis-related DE-mRNAs. Ferroptosis-related DE-mRNAs of gene ontology terms and Encyclopedia of Genes and Genomes pathway enrichment analysis were enriched significantly in response to oxidative stress and ferroptosis. Five hub genes (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) were found in the constructed protein-protein interaction network with ferroptosis-related DE-mRNAs and the areas under the ROC curves for ALB, NOX4, CDKN2A, TXNRD1, and CAV1 were 0.938 (CI: 0.815-1.000), 0.833 (CI: 0.612-1.000), 0.875 (CI: 0.704-1.000), 0.958 (CI: 0.862-1.000), and 0.854 (CI: 0.652-1.000) in univariate analysis of ROC. We constructed a regulatory network of miRNA-hub gene and the findings demonstrate that hsa-miR-26b-5p, hsa-miR-192-5p, hsa-miR-124-3p, hsa-miR-492, hsa-miR-34a-5p and hsa-miR-155-5p could regulate most hub genes. In this study, we identified several central genes closely related to ferroptosis in STB-EVs (ALB, NOX4, CDKN2A, TXNRD1, and CAV1) that are potential biomarkers related to ferroptosis in preeclampsia. Our findings will provide evidence for the involvement of ferroptosis in preeclampsia and improve the understanding of ferroptosis-related molecular pathways in the pathogenesis of preeclampsia.

Project description:BackgroundPlatelet (Plt)-derived extracellular vesicles (Plt-EVs) have hemostatic properties similar to Plts. In addition to hemostasis, Plts also function to stabilize the vasculature and maintain endothelial cell (EC) barrier integrity. We hypothesized that Plt-EVs would inhibit vascular EC permeability, similar to fresh Plts. To investigate this hypothesis, we used in vitro and in vivo models of vascular endothelial compromise and bleeding.MethodsIn the vitro model, Plt-EVs were isolated by ultracentrifugation and characterized for Plt markers and particle size distribution. Effects of Plts and Plt-EVs on endothelial barrier function were assessed by transendothelial electrical resistance measurements and histological analysis of endothelial junction proteins. Hemostatic potential of Plt-EVs and Plts was assessed by multiple electrode Plt aggregometry. Using an in vivo model, the effects of Plts and Plt-EVs on vascular permeability and bleeding were assessed in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice by an established Miles assay of vascular permeability and a tail snip bleeding assay.ResultsIn the in vitro model, Plt-EVs displayed exosomal size distribution and expressed Plt-specific surface markers. Platelets and Plt-EVs decreased EC permeability and restored EC junctions after thrombin challenge. Multiplate aggregometry revealed that Plt-EVs enhanced thrombin receptor-activating peptide-mediated aggregation of whole blood, whereas Plts enhanced thrombin receptor-activating peptide-, arachidonic acid-, collagen-, and adenosine diphosphate-mediated aggregation. In the in vivo model, Plt-EVs are equivalent to Plts in attenuating vascular endothelial growth factor (VEGF)-A-induced vascular permeability and uncontrolled blood loss in a tail snip hemorrhage model.ConclusionOur study is the first to report that Plt-EVs might provide a feasible product for transfusion in trauma patients to attenuate bleeding, inhibit vascular permeability, and mitigate the endotheliopathy of trauma.

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Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells.

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Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells.

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