| 1. |
- Moberg, Christian, et al.
(författare)
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VEGF-A and Serum Withdrawal Induced Changes in the Transcript Profile in Human Endometrial Endothelial Cells
- 2010
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Ingår i: Reproductive Sciences. - : Springer Science and Business Media LLC. - 1933-7191 .- 1933-7205. ; 17:6, s. 590-611
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Tidskriftsartikel (refereegranskat)abstract
- The changes in transcript profile induced by vascular endothelial growth factor (VEGF-A) and serum withdrawal in primary human endometrial endothelial cells (ECs) were investigated using microarrays, gene ontology and pathway analysis. Vascular endothelial growth factor A altered the levels of transcripts involved in angiogenesis, cell survival, and apoptosis, including up-and downregulation of AKT1, BAD, MIF, and IGFBP3 and ANGPT2, respectively. Serum deprivation induced downregulation of cell-cycle-related transcripts such as mitosis regulators CDC20 and SPC25. Of the transcripts regulated by both VEGF-A and partial serum deprivation, remarkably 88 of 89 showed reciprocal regulation (p < 1 x 10(-49)). These are predominantly cell-fate-associated transcripts and this novel observation suggests that endometrial ECs may be particularly dependant on the levels of these transcripts. Our results show that in addition to the known role of VEGF-A as an EC growth and survival promoter, it also regulates apoptosis-related messenger RNAs (mRNAs), many of which were reciprocally regulated following serum withdrawal.
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| 2. |
- Yung, Hong Wa, et al.
(författare)
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Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism
- 2023
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Ingår i: iScience. - : Cell Press. - 2589-0042. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with "protein glycosylation"and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.
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| 3. |
- Aswad, Amr, et al.
(författare)
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Evolutionary history of endogenous Human Herpesvirus 6 reflects human migration out of Africa
- 2021
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Ingår i: Molecular biology and evolution. - : Oxford University Press. - 0737-4038 .- 1537-1719. ; 38:1, s. 96-107
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Tidskriftsartikel (refereegranskat)abstract
- Human herpesvirus 6A and 6B (HHV-6) can integrate into the germline, and as a result about 70 million people harbour the genome of one of these viruses in every cell of their body. Until now, it has been largely unknown if i) these integrations are ancient, ii) if they still occur, and iii) whether circulating virus strains differ from integrated ones. Here we used next generation sequencing and mining of public human genome datasets to generate the largest and most diverse collection of circulating and integrated HHV-6 genomes studied to date. In genomes of geographically dispersed, only distantly-related people, we identified clades of integrated viruses that originated from a single ancestral event, confirming this with fluorescent in situ hybridization to directly observe the integration locus. In contrast to HHV-6B, circulating and integrated HHV-6A sequences form distinct clades, arguing against ongoing integration of circulating HHV-6A or "reactivation" of integrated HHV-6A. Taken together, our study provides the first comprehensive picture of the evolution of HHV-6, and reveals that integration of heritable HHV-6 has occurred since the time of, if not before, human migrations out of Africa.
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| 4. |
- Carmeliet, Peter, et al.
(författare)
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Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions
- 2001
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:5, s. 575-583
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf-/-). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf-/- mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf-/- mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.
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| 5. |
- de Goffau, Marcus C., et al.
(författare)
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Human placenta has no microbiome but can contain potential pathogens
- 2019
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 572:7769, s. 329-334
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Tidskriftsartikel (refereegranskat)abstract
- We sought to determine whether pre-eclampsia, spontaneous preterm birth or the delivery of infants who are small for gestational age were associated with the presence of bacterial DNA in the human placenta. Here we show that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies. Almost all signals were related either to the acquisition of bacteria during labour and delivery, or to contamination of laboratory reagents with bacterial DNA. The exception was Streptococcus agalactiae (group B Streptococcus), for which non-contaminant signals were detected in approximately 5% of samples collected before the onset of labour. We conclude that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.
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| 6. |
- Gaccioli, Francesca, et al.
(författare)
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Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia
- 2020
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Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 5:7, s. 901-908
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Tidskriftsartikel (refereegranskat)abstract
- Pre-eclampsia (typically characterized by new-onset hypertension and proteinuria in the second half of pregnancy) represents a major determinant of the global burden of disease1,2. Its pathophysiology involves placental dysfunction, but the mechanism is unclear. Viral infection can cause organ dysfunction, but its role in placentally related disorders of human pregnancy is unknown3. We addressed this using RNA sequencing metagenomics4-6 of placental samples from normal and complicated pregnancies. Here, we show that human herpesvirus 6 (HHV-6, A or B) RNA was detected in 6.1% of cases of pre-eclampsia and 2.2% of other pregnancies. Fetal genotyping demonstrated that 70% of samples with HHV-6 RNA in the placenta exhibited inherited, chromosomally integrated HHV-6 (iciHHV-6). We genotyped 467 pre-eclampsia cases and 3,854 controls and found an excess of iciHHV-6 in the cases (odds ratio of 2.8, 95% confidence intervals of 1.4-5.6, P = 0.008). We validated this finding by comparing iciHHV-6 in a further 740 cases with controls from large-scale population studies (odds ratio of 2.5, 95% confidence intervals of 1.4-4.4, P = 0.0013). We conclude that iciHHV-6 results in the transcription of viral RNA in the human placenta and predisposes the mother to pre-eclampsia.
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| 7. |
- Gaccioli, Francesca, et al.
(författare)
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Placental Streptococcus agalactiae DNA is associated with neonatal unit admission and foetal pro-inflammatory cytokines in term infants
- 2023
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Ingår i: Nature Microbiology. - : Springer Nature. - 2058-5276. ; 8:12, s. 2338-2348
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus agalactiae (Group B Streptococcus; GBS) is a common cause of sepsis in neonates. Previous work detected GBS DNA in the placenta in ~5% of women before the onset of labour, but the clinical significance of this finding is unknown. Here we re-analysed this dataset as a case control study of neonatal unit (NNU) admission. Of 436 infants born at term (≥37 weeks of gestation), 7/30 with placental GBS and 34/406 without placental GBS were admitted to the NNU (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.3-7.8). We then performed a validation study using non-overlapping subjects from the same cohort. This included a further 239 cases of term NNU admission and 686 term controls: 16/36 with placental GBS and 223/889 without GBS were admitted to the NNU (OR 2.4, 95% CI 1.2-4.6). Of the 36 infants with placental GBS, 10 were admitted to the NNU with evidence of probable but culture-negative sepsis (OR 4.8, 95% CI 2.2-10.3), 2 were admitted with proven GBS sepsis (OR 66.6, 95% CI 7.3-963.7), 6 were admitted and had chorioamnionitis (inflammation of the foetal membranes) (OR 5.3, 95% CI 2.0-13.4), and 5 were admitted and had funisitis (inflammation of the umbilical cord) (OR 6.7, 95% CI 12.5-17.7). Foetal cytokine storm (two or more pro-inflammatory cytokines >10 times median control levels in umbilical cord blood) was present in 36% of infants with placental GBS DNA and 4% of cases where the placenta was negative (OR 14.2, 95% CI 3.6-60.8). Overall, ~1 in 200 term births had GBS detected in the placenta, which was associated with infant NNU admission and morbidity.
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| 8. |
- Lager, Susanne, et al.
(författare)
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Abnormal placental CD8+ T cell infiltration is a feature of fetal growth restriction and pre-eclampsia.
- 2020
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Ingår i: Journal of Physiology. - 0022-3751 .- 1469-7793. ; 598:23, s. 5555-5571
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Tidskriftsartikel (refereegranskat)abstract
- KEY POINTS: Placental pathological abnormalities are more frequently observed in complicated pregnancies than in healthy pregnancies Infiltration of CD8+ T-cells into the placental villous tissue occurred in both fetal growth restriction and pre-eclampsia, whereas CD79α+ B-cell infiltration was only apparent with reduced fetal growth. Vascularisation, fibrin depositions, macrophage and neutrophil infiltration in the placenta did not differ between healthy and complicated pregnancies.ABSTRACT: Fetal growth restriction (FGR) and pre-eclampsia are severe, adverse pregnancy outcomes. Alterations in placental histology are frequently reported in these pregnancy complications and are often based upon scoring by pathologists. However, many alterations are also observed in placenta from uncomplicated pregnancies. Moreover, knowledge of disease state may bias assessment. We sought to perform an objective comparison of placental microscopic appearance in normal and complicated pregnancies. Placental villous tissue (n = 823) and edge biopsies (n = 488) from 871 individual, singleton pregnancies were collected after delivery. Cases of small-for-gestational-age (SGA) or pre-eclampsia were matched with healthy controls. A subset of the SGA cases displayed signs of FGR. Cases of pre-term delivery were also included. Tissue sections were stained with H&E or antibodies for CD8, CD14, CD31, CD79α, elastase. Images were scored by two experienced pathologists for pathological features or analysed by image analysis and stereology. Analyses were performed blind to case-control status and gestational age. Volume fraction of T-cells increased in placentas from pregnancies complicated by pre-eclampsia (adjusted odds ratio (aOR) 1.46, 95% CI 1.12-1.90) and FGR (aOR 1.64, 95% CI 1.11-2.43), whereas B-cells only increased in FGR (aOR 1.65, 95% CI 1.05-2.60). Pathological abnormalities in villous tissue were reported in 21.4% (88/411) of complicated pregnancies and 14.3% (52/363) of controls (OR 1.62, 95% CI 1.12-2.37). There were no differences in the fractions of endothelial cells, fibrin deposition, macrophages, and neutrophils when comparing normal and complicated pregnancies. In conclusion, FGR and pre-eclampsia are associated with T-cell infiltration of the placenta and placental pathological abnormalities. This article is protected by copyright. All rights reserved.
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| 9. |
- Mizuuchi, Masahito, et al.
(författare)
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Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6β : implications for the pathophysiology of human pregnancy complications
- 2016
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 238:4, s. 550-561
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Tidskriftsartikel (refereegranskat)abstract
- Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early-onset pre-eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high-risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early-onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down-regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6α and ATF6β in the syncytiotrophoblast of placentas from PE patients. Transcript analysis showed a decrease of PlGF mRNA, and an increase from genes encoding those UPR transcription factors, in placentas from cases of early-onset PE, but not in the late-onset (>34 weeks) PE, compared to term controls. Further investigations indicated a strong correlation between ATF4 and PlGF mRNA levels only (r = -0.73, p<0.05). These results could be recapitulated in trophoblast-like cells exposed to chemical inducers of ER stress or hypoxia/reoxygenation. The stability of PlGF transcripts was unchanged. The use of small interfering RNA specific for transcription factors in the UPR pathways revealed that ATF4 and ATF6β, but not ATF6α, modulate PlGF transcription. To conclude, ATF4 and ATF6β act synergistically in the negative regulation of PlGF mRNA expression, resulting in reduced PlGF secretion by the trophoblast in response to stress. Therefore, these results further support targeting of placental ER stress as a potential new therapeutic intervention for these pregnancy complications.
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| 10. |
- Yung, Hong Wa, et al.
(författare)
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Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia
- 2014
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 234:2, s. 262-276
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Tidskriftsartikel (refereegranskat)abstract
- Based on gestational age at diagnosis and/or delivery, pre-eclampsia (PE) is commonly divided into early-onset (<34 weeks) and late-onset (>= 34 weeks) forms. Recently, the distinction between 'placental' and 'maternal' causation has been proposed, with 'placental' cases being more frequently associated with early-onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress-signalling pathways, including unfolded protein response (UPR) pathways, MAPK stress pathways, heat-shock proteins and AMPK.. in placentae delivered by caesarean section for clinical indications at different gestational ages. Controls included second-trimester, pre-term and normal-term placentae. BeWo cells were used to investigate how these pathways react to different severities of hypoxia-reoxygenation (H/R) and pro-inflammatory cytokines. Activation of placental UPR and stress-response pathways, including P-IRE1 alpha, ATF6, XBP-1, GRP78 and GRP94, P-p38/p38 and HSP70, was higher in early-onset PE than in both late-onset PE and normotensive controls (NTCs), with a clear inflection around 34 weeks. Placentae from >= 34 weeks PE and NTC were indistinguishable. Levels of UPR signalling were similar between second-trimester and term controls, but were significantly higher in pre-term 'controls' delivered vaginally for chorioamnionitis and other conditions. Severe H/R (1/20% O-2) induced equivalent activation of UPR pathways, including P-eIF2 alpha, ATF6, P-IRE1 alpha, GRP78 and GRP94, in BeWo cells. By contrast, the pro-inflammatory cytokines TNF alpha and IL-1 beta induced only mild activation of P-eIF2 alpha and GRP78. AKT, a central regulator of cell proliferation, was reduced in the <34 weeks PE placentae and severe H/R-treated cells, but not in other conditions. These findings provide the first molecular evidence that placental stress may contribute to the pathophysiology of early-onset pre-eclampsia, whereas that is unlikely to be the case in the late-onset form of the syndrome. (c) 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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