Placental expression of sFlt-1 and PlGF in early preeclampsia vs. early IUGR vs. age-matched healthy pregnancies

Hoeller, Alice; Ehrlich, Laura; Golić, Michaela; Herse, Florian; Perschel, F. H.; Siwetz, Monika; Henrich, Wolfgang; Dechend, Ralf; Huppertz, Berthold; Verlohren, Stefan

doi:10.1080/10641955.2016.1273363

Cited by 39 publications

(27 citation statements)

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“…In-depth analyses of the differences in FGR placenta that revealed candidate genes and pathways that fit previously reported histopathological and protein data. For example, we found hyperacetylation and higher mRNA of the sFlt-1 region in FGR placentas, consistent with studies reporting upregulation of sFlt-1 protein in FGR placentas [ 36 , 37 ]. Furthermore, sFlt-1 is known to be enriched in syncytial knots, which are also observed in FGR placenta [ 38 ].…”

Section: Discussionsupporting

confidence: 91%

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

et al. 2018

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BackgroundPosttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes.ResultsAnalysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1.ConclusionWe demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0508-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

et al. 2018

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“…Specifically, exposure to PFOS, PFOA, and HFPO‐DA resulted in decreased expression of all four of the proliferation markers measured, although this trend was significant only in the case of PLGF in SFM. This is of particular interest because expression PLGF , which regulates trophoblast proliferation as well as angiogenesis, has been shown in both maternal serum and placenta to be inversely associated with preeclampsia 43,44 . In addition, pro‐apoptotic markers BAD and BAX were up‐regulated and anti‐apoptotic BCL2 was down‐regulated in both SFM and SSM after exposure to PFOA, PFOS, or HFPO‐DA.…”

Section: Discussionmentioning

confidence: 99%

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Bangma

Szilagyi

Blake

et al. 2020

Environmental Toxicology

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Per‐ and polyfluoroalkyl substances (PFAS), a class of environmental contaminants, have been detected in human placenta and cord blood. The mechanisms driving PFAS‐induced effects on the placenta and adverse pregnancy outcomes are not well understood. This study investigated the impact of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and a replacement PFAS known as hexafluoropropylene oxide dimer acid (HFPO‐DA, tradename GenX) on placental trophoblasts in vitro. Several key factors were addressed. First, PFAS levels in cell culture reagents at baseline were quantified. Second, the role of supplemental media serum in intracellular accumulation of PFAS in a human trophoblast (JEG3) cell line was established. Finally, the impact of PFAS on the expression of 96 genes involved in proper placental function in JEG3 cells was evaluated. The results revealed that serum‐free media (SFM) contained no detectable PFAS. In contrast, fetal bovine serum‐supplemented media (SSM) contained PFNA, PFUdA, PFTrDA, and 6:2 FTS, but these PFAS were not detected internally in cells. Intracellular accumulation following 24 hr treatments was significantly higher when cultured in SFM compared to SSM for PFOS and PFOA, but not HFPO‐DA. Treatment with PFAS was associated with gene expression changes (n = 32) in pathways vital to placental function, including viability, syncytialization, inflammation, transport, and invasion/mesenchymal transition. Among the most robust PFAS‐associated changes were those observed in the known apoptosis‐related genes, BAD and BAX. These results suggest a complex relationship between PFAS, in vitro culture conditions, and altered expression of key genes necessary for proper placentation.

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“…Expression of PlGF is postulated to be lowered due to suppression by persistent placental hypoxia resulting from an underdeveloped utero-placental circulation. However, studies have also shown increased 3 or no change in PlGF expression 22 in pre-eclamptic placental tissue. Regulation of PlGF expression is unclear, but several mechanisms have been explored such as endoplasmic reticulum stress and epigenetic changes altering the effect of the transcription factor hypoxia-inducible factor-1α (HIF1-α), although the role of HIF1-α in trophoblast growth is debated.…”

Section: Plgf In Pre-eclampsiamentioning

confidence: 99%

Placental growth factor and pre-eclampsia

2017

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Placental growth factor (PlGF) is an increasingly important molecule in the prediction, diagnosis and treatment of pre-eclampsia. It has pro-angiogenic effects on the feto-placental circulation and supports trophoblast growth. Mechanisms by which PlGF expression is regulated continue to be investigated. Low circulating PlGF precedes the manifestation of clinical disease in pre-eclamptic pregnancies and intrauterine growth restriction. This suggests that low PlGF is a marker of abnormal placentation, but it remains uncertain whether this is a cause or consequence. Prediction of pre-eclampsia using PlGF is promising and may assist in the targeting of resources to women at highest risk of adverse pregnancy outcomes. Promisingly, experimental animal models of pre-eclampsia have been successfully treated with supplemental PlGF. Treatment of pre-eclampsia with PlGF is a potential therapeutic option requiring further exploration. This review focuses specifically on the role of PlGF in normal and pathological placental development and in the clinical management of pre-eclampsia.

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Placental expression of sFlt-1 and PlGF in early preeclampsia vs. early IUGR vs. age-matched healthy pregnancies

Abstract: High sFlt-1 concentrations may account for diminished maternal serum PlGF levels.

Cited by 39 publications

References 30 publications

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction

An assessment of serum‐dependent impacts on intracellular accumulation and genomic response of per‐ and polyfluoroalkyl substances in a placental trophoblast model

Placental growth factor and pre-eclampsia

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