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1.
Medicina (Kaunas) ; 57(6)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064060

RESUMO

Background and Objectives: Therapeutic interventions targeting molecular factors involved in the transition from uterine quiescence to overt labour are not substantially reducing the rate of spontaneous preterm labour. The identification of novel rational therapeutic targets are essential to prevent the most common cause of neonatal mortality. Based on our previous work showing that Tbx2 (T-Box transcription factor 2) is a putative upstream regulator preceding progesterone withdrawal in mouse myometrium, we now investigate the role of TBX2 in human myometrium. Materials and Methods: RNA microarray analysis of (A) preterm human myometrium samples and (B) myometrial cells overexpressing TBX2 in vitro, combined with subsequent analysis of the two publicly available datasets of (C) Chan et al. and (D) Sharp et al. The effect of TBX2 overexpression on cytokines/chemokines secreted to the myometrium cell culture medium were determined by Luminex assay. Results: Analysis shows that overexpression of TBX2 in myometrial cells results in downregulation of TNFα- and interferon signalling. This downregulation is consistent with the decreased expression of cytokines and chemokines of which a subset has been previously associated with the inflammatory pathways relevant for human labour. In contrast, CXCL5 (C-X-C motif chemokine ligand 5), CCL21 and IL-6 (Interleukin 6), previously reported in relation to parturition, do not seem to be under TBX2 control. The combined bioinformatical analysis of the four mRNA datasets identifies a subset of upstream regulators common to both preterm and term labour under control of TBX2. Surprisingly, TBX2 mRNA levels are increased in preterm contractile myometrium. Conclusions: We identified a subset of upstream regulators common to both preterm and term labour that are activated in labour and repressed by TBX2. The increased TBX2 mRNA expression in myometrium collected during a preterm caesarean section while in spontaneous preterm labour compared to tissue harvested during iatrogenic preterm delivery does not fit the bioinformatical model. We can only explain this by speculating that the in vivo activity of TBX2 in human myometrium depends not only on the TBX2 expression levels but also on levels of the accessory proteins necessary for TBX2 activity.


Assuntos
Trabalho de Parto , Trabalho de Parto Prematuro , Cesárea , Feminino , Humanos , Interleucina-6 , Miométrio , Trabalho de Parto Prematuro/genética , Gravidez , Proteínas com Domínio T
2.
Front Cell Dev Biol ; 9: 671806, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34095140

RESUMO

Mutations in the LINC-HELLP non-coding RNA (HELLPAR) have been associated with familial forms of the pregnancy-specific HELLP syndrome. These mutations negatively affect extravillous trophoblast (EVT) differentiation from a proliferative to an invasive state and disturb the binding of RNA splicing complex proteins PCBP1, PCBP2, and YBX1 to LINC-HELLP. In this study, by using both in vitro and ex vivo experiments, we investigate if these proteins are involved in the regulation of EVT invasion during placentation. Additionally, we study if this regulation is due to alternative mRNA splicing. HTR-8/SVneo extravillous trophoblasts and human first trimester placental explants were used to investigate the effect of siRNA-mediated downregulation of PCBP1, PCBP2, and YBX1 genes on the differentiation of EVTs. Transwell invasion assays and proliferation assays indicated that upon knockdown of PCBP2 and, to a lesser extent, YBX1 and PCBP1, EVTs fail to differentiate toward an invasive phenotype. The same pattern was observed in placental explants where PCBP2 knockdown led to approximately 80% reduction in the number of explants showing any EVT outgrowth. Of the ones that still did show EVT outgrowth, the percentage of proliferating EVTs was significantly higher compared to explants transfected with non-targeting control siRNAs. To further investigate this effect of PCBP2 silencing on EVTs, we performed whole transcriptome sequencing (RNA-seq) on HTR-8/SVneo cells after PCBP2 knockdown. PCBP2 knockdown was found to have minimal effect on mRNA expression levels. In contrast, PCBP2 silencing led to a switch in splicing for a large number of genes with predominant functions in cellular assembly and organization, cellular function and maintenance, and cellular growth and proliferation and the cell cycle. EVTs, upon differentiation, alter their function to be able to invade the decidua of the mother by changing their cellular assembly and their proliferative activity by exiting the cell cycle. PCBP2 appears to be a paramount regulator of these differentiation mechanisms, where its disturbed binding to LINC-HELLP could contribute to dysfunctional placental development as seen in the HELLP syndrome.

3.
Hum Reprod ; 35(8): 1797-1807, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32644109

RESUMO

STUDY QUESTION: How do high-quality human preimplantation embryos influence the endometrium to promote their own implantation? SUMMARY ANSWER: High-quality human preimplantation embryos secrete a specific microRNA (miRNA), hsa-miR-320a, which promotes migration of human endometrial stromal cells (hESCs). WHAT IS KNOWN ALREADY: We have previously shown that high-quality human preimplantation embryos excrete unknown factors that influence migration of hESCs. STUDY DESIGN, SIZE, DURATION: Embryo excreted miRNAs, specifically those excreted by high-quality embryos, were identified and their effect on hESCs was determined by measuring the migration capacity and gene expression patterns of primary isolated hESCs. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryo conditioned medium (ECM) from routine ICSI procedures was used to identify embryo excreted miRNAs. miRNome analyses were performed on ECM from individually cultured embryos with high morphological quality, with low morphological quality or empty control medium. MiRNA mimics and inhibitors were then used to further study the effect of miRNAs of interest on migration and gene expression of hESCs. Migration assays were performed using hESCs that were obtained from endometrial biopsies performed on hysterectomy specimens from women that received surgery for spotting due to a niche in a cesarean section scar. MAIN RESULTS AND THE ROLE OF CHANCE: By using miRNA mimics and inhibitors, we showed that hsa-miR-320a alone can stimulate migration of decidualized hESCs, accurately resembling the response typically triggered only by high-quality embryos. Transcriptome analysis further demonstrated that this effect is very likely mediated via altered expression of genes involved in cell adhesion and cytoskeleton organization. LIMITATIONS, REASONS FOR CAUTION: The effect of hsa-miR-320a on hESCs was measured in vitro. Further studies on the in vivo effect of hsa-miR-320a are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Implantation failure is one of the major success limiting factors in human reproduction. By secreting hsa-miR-320a, high-quality human preimplantation embryos directly influence hESCs, most likely to prime the endometrium at the implantation site for successful implantation. Together, our results indicate that hsa-miR-320a may be a promising target to further increase success rates in assisted reproduction. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Amsterdam University Medical Centers and the Amsterdam Reproduction & Development Research Institute. R.P.B., G.H. and S.M. have a patent on the use of hsa-miR-320a in assisted reproduction treatments pending. TRIAL REGISTRATION NUMBER: N/A.


Assuntos
Cesárea , MicroRNAs , Blastocisto , Movimento Celular , Endométrio , Feminino , Humanos , MicroRNAs/genética , Gravidez , Células Estromais
4.
Pregnancy Hypertens ; 19: 100-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31927322

RESUMO

OBJECTIVES: Ceramide is a sphingolipid with anti-angiogenic and pro-apoptotic properties that has shown to be increased in plasma of women with pre-eclampsia. We aimed to compare plasma and placental sphingolipid content among normotensive pregnant women and pre-eclamptic women with and without HELLP syndrome and we aimed to assess whether ceramide is related to hypertension and proteinuria in pre-eclampsia. STUDY DESIGN: Case-control study. Participants were recruited from the Department of Obstetrics at the Academic Medical Center in Amsterdam, The Netherlands. In total 48 pregnant women were included: 24 with pre-eclampsia and 24 normotensive controls. Of the 24 pre-eclamptic women, 11 had HELLP syndrome. MAIN OUTCOME MEASURES: Plasma and placental ceramide content and correlation with blood pressure and protein excretion in pre-eclampsia. RESULTS: Total plasma, but not placental, ceramide was higher in pre-eclamptic women with HELLP syndrome (11200 95% CI 9531-12870 nmol/ml, n = 11) compared to pre-eclamptic women without HELLP (7413 95% CI 5928-8898 nmol/ml, n = 13, p < 0.001) and normotensive pregnant women (7404 95% CI 6695-8112 nmol/ml, n = 24, p < 0.001). Maternal circulating ceramide levels were strongly associated with proteinuria (r = 0.621, n = 24, p = 0.001) in pre-eclamptic women and inversely correlated with gestational age at delivery (r = 0.771, p < 0.01) in pre-eclamptic women with HELLP syndrome. Plasma ceramide was not correlated with blood pressure. CONCLUSION: Plasma but not placental ceramide content is increased in women with pre-eclampsia and HELLP syndrome. The strong positive correlation with proteinuria and the inverse correlation with gestational age at delivery indicate that excess plasma ceramide may contribute to the pathophysiology of pre-eclampsia and HELLP.


Assuntos
Ceramidas/metabolismo , Síndrome HELLP/sangue , Pré-Eclâmpsia/sangue , Proteinúria/sangue , Adulto , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Placenta/metabolismo , Contagem de Plaquetas , Gravidez
5.
Sci Rep ; 9(1): 19077, 2019 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836787

RESUMO

Preeclampsia is a frequent gestational hypertensive disorder with equivocal pathophysiology. Knockout of peptide hormone ELABELA (ELA) has been shown to cause preeclampsia-like symptoms in mice. However, the role of ELA in human placentation and whether ELA is involved in the development of preeclampsia in humans is not yet known. In this study, we show that exogenous administration of ELA peptide is able to increase invasiveness of extravillous trophoblasts in vitro, is able to change outgrowth morphology and reduce trophoblast proliferation ex vivo, and that these effects are, at least in part, independent of signaling through the Apelin Receptor (APLNR). Moreover, we show that circulating levels of ELA are highly variable between women, correlate with BMI, but are significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia. We conclude that the large variability and BMI dependence of ELA levels in circulation make this peptide an unlikely candidate to function as a first trimester preeclampsia screening biomarker, while in the future administering ELA or a derivative might be considered as a potential preeclampsia treatment option as ELA is able to drive extravillous trophoblast differentiation.


Assuntos
Diferenciação Celular , Hormônios Peptídicos/sangue , Placenta/metabolismo , Trofoblastos/citologia , Adulto , Apelina/sangue , Índice de Massa Corporal , Linhagem Celular , Proliferação de Células , Estudos de Coortes , Feminino , Humanos , Pré-Eclâmpsia/sangue , Gravidez , Primeiro Trimestre da Gravidez/sangue , Gêmeos
6.
Pregnancy Hypertens ; 17: 148-157, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31487633

RESUMO

The apelinergic-axis (Apelin, Elabela and their receptor APJ) is involved in many physiological and pathological processes. Both Elabela/APJ and Apelin/APJ are implicated in the pathophysiology of preeclampsia in rodents. However, the findings regarding the apelinergic axis in human preeclamptic placental development have been rather conflicting. In this systematic review we present an overview of the current evidence regarding the pathophysiological role of Apelin, Elabela and their receptor in human preeclamptic pregnancies. The databases used for this systematic review were Pubmed, Scopus, Google Scholar and ClinicalTrials.gov. The reference lists of the selected studies were also screened for any additional studies. The last search was performed on the 25th of March 2019. Thirteen studies were included and subjected to quality assessment so that only high quality datasets were finally selected and included in this systematic evaluation. In total, 410 women that developed preeclampsia or IUGR and 409 healthy control pregnancies were included. The findings of this review suggest that circulating Apelin levels are increased in early onset/severe preeclamptic patients while Apelin levels in severe preeclamptic placenta tissues appear to show the opposite. Circulating Elabela levels in early-onset preeclamptic women do not differ from controls, while its levels in late-onset preeclampsia remain inconclusive. The studies on Elabela and APJ expression in placental tissues require larger sample sizes with defined preeclampsia subtypes to draw any definite conclusions. Large cohort studies with affected and control groups matched for Body Mass Index and gestational age at sampling are essential in order to substantiate other current findings.


Assuntos
Receptores de Apelina/metabolismo , Apelina/metabolismo , Hormônios Peptídicos/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Feminino , Humanos , Pré-Eclâmpsia/sangue , Gravidez
7.
Proc Natl Acad Sci U S A ; 116(36): 17800-17808, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31431534

RESUMO

Endoglin (ENG) is a coreceptor of the transforming growth factor-ß (TGFß) family signaling complex, which is highly expressed on endothelial cells and plays a key role in angiogenesis. Its extracellular domain can be cleaved and released into the circulation as soluble ENG (sENG). High circulating levels of sENG contribute to the pathogenesis of preeclampsia (PE). Circulating bone morphogenetic protein 9 (BMP9), a vascular quiescence and endothelial-protective factor, binds sENG with high affinity, but how sENG participates in BMP9 signaling complexes is not fully resolved. sENG was thought to be a ligand trap for BMP9, preventing type II receptor binding and BMP9 signaling. Here we show that, despite cell-surface ENG being a dimer linked by disulfide bonds, sENG purified from human placenta and plasma from PE patients is primarily in a monomeric form. Incubating monomeric sENG with the circulating form of BMP9 (prodomain-bound form) in solution leads to the release of the prodomain and formation of a sENG:BMP9 complex. Furthermore, we demonstrate that binding of sENG to BMP9 does not inhibit BMP9 signaling. Indeed, the sENG:BMP9 complex signals with comparable potency and specificity to BMP9 on human primary endothelial cells. The full signaling activity of the sENG:BMP9 complex required transmembrane ENG. This study confirms that rather than being an inhibitory ligand trap, increased circulating sENG might preferentially direct BMP9 signaling via cell-surface ENG at the endothelium. This is important for understanding the role of sENG in the pathobiology of PE and other cardiovascular diseases.


Assuntos
Endoglina/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Proteínas da Gravidez/metabolismo , Transdução de Sinais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez
8.
Wellcome Open Res ; 3: 123, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30345390

RESUMO

Background: Although nausea and vomiting are very common in pregnancy, their pathogenesis is poorly understood. We tested the hypothesis that circulating growth and differentiation factor 15 (GDF15) concentrations in early pregnancy, whose gene is implicated in hyperemesis gravidarum, are associated with nausea and vomiting. Methods: Blood samples for the measurement of GDF15 and human chorionic gonadotrophin (hCG) concentrations were obtained early in the second trimester (median 15.1 (interquartile range 14.4-15.7) weeks) of pregnancy from 791 women from the Cambridge Baby Growth Study, a prospective pregnancy and birth cohort. During each trimester participants completed a questionnaire which included questions about nausea, vomiting and antiemetic use. Associations with pre-pregnancy body mass indexes (BMI) were validated in 231 pregnant NIPTeR Study participants. Results: Circulating GDF15 concentrations were higher in women reporting vomiting in the second trimester than in women reporting no pregnancy nausea or vomiting: 11,581 (10,977-12,219) (n=175) vs. 10,593 (10,066-11,147) (n=193) pg/mL, p=0.02). In women who took antiemetic drugs during pregnancy (n=11) the GDF15 levels were also raised 13,157 (10,558-16,394) pg/mL (p =0.04). Serum GFD15 concentrations were strongly positively correlated with hCG levels but were inversely correlated with maternal BMIs, a finding replicated in the NIPTeR Study. Conclusions: Week 15 serum GDF15 concentrations are positively associated with second trimester vomiting and maternal antiemetic use in pregnancy. Given GDF15's site of action in the chemoreceptor trigger zone of the brainstem and its genetic associations with hyperemesis gravidarum, these data support the concept that GDF15 may be playing a pathogenic role in pregnancy-associated vomiting.

9.
Science ; 357(6352): 707-713, 2017 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-28663440

RESUMO

Preeclampsia (PE) is a gestational hypertensive syndrome affecting between 5 and 8% of all pregnancies. Although PE is the leading cause of fetal and maternal morbidity and mortality, its molecular etiology is still unclear. Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. In mice, infusion of exogenous ELA normalizes hypertension, proteinuria, and birth weight. ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE. The ELA-APLNR signaling axis may offer a new paradigm for the treatment of common pregnancy-related complications, including PE.


Assuntos
Anormalidades Cardiovasculares/genética , Proteínas de Transporte/genética , Hormônios Placentários/genética , Placentação/genética , Pré-Eclâmpsia/genética , Animais , Apelina/genética , Apelina/metabolismo , Peso ao Nascer , Proteínas de Transporte/administração & dosagem , Proteínas de Transporte/metabolismo , Proteínas de Transporte/farmacologia , Feminino , Camundongos , Camundongos Knockout , Neovascularização Fisiológica/genética , Hormônios Peptídicos , Placenta/irrigação sanguínea , Placenta/metabolismo , Gravidez , Proteinúria , Transdução de Sinais
10.
BMC Genomics ; 16: 736, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26419829

RESUMO

BACKGROUND: Preterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05. RESULTS: The analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery. 1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation. Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified. CONCLUSION: This study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Sangue Fetal , Trabalho de Parto Prematuro/genética , Feminino , Genoma Humano , Humanos , Recém-Nascido , Masculino , Trabalho de Parto Prematuro/patologia , Ocitocina/genética , Gravidez
11.
PLoS One ; 10(7): e0132468, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26171964

RESUMO

Studies using the placental transcriptome to identify key molecules relevant for preeclampsia are hampered by a relatively small sample size. In addition, they use a variety of bioinformatics and statistical methods, making comparison of findings challenging. To generate a more robust preeclampsia gene expression signature, we performed a meta-analysis on the original data of 11 placenta RNA microarray experiments, representing 139 normotensive and 116 preeclamptic pregnancies. Microarray data were pre-processed and analyzed using standardized bioinformatics and statistical procedures and the effect sizes were combined using an inverse-variance random-effects model. Interactions between genes in the resulting gene expression signature were identified by pathway analysis (Ingenuity Pathway Analysis, Gene Set Enrichment Analysis, Graphite) and protein-protein associations (STRING). This approach has resulted in a comprehensive list of differentially expressed genes that led to a 388-gene meta-signature of preeclamptic placenta. Pathway analysis highlights the involvement of the previously identified hypoxia/HIF1A pathway in the establishment of the preeclamptic gene expression profile, while analysis of protein interaction networks indicates CREBBP/EP300 as a novel element central to the preeclamptic placental transcriptome. In addition, there is an apparent high incidence of preeclampsia in women carrying a child with a mutation in CREBBP/EP300 (Rubinstein-Taybi Syndrome). The 388-gene preeclampsia meta-signature offers a vital starting point for further studies into the relevance of these genes (in particular CREBBP/EP300) and their concomitant pathways as biomarkers or functional molecules in preeclampsia. This will result in a better understanding of the molecular basis of this disease and opens up the opportunity to develop rational therapies targeting the placental dysfunction causal to preeclampsia.


Assuntos
Perfilação da Expressão Gênica/métodos , Placenta/metabolismo , Pré-Eclâmpsia/genética , Feminino , Humanos , Pré-Eclâmpsia/metabolismo , Gravidez , Mapeamento de Interação de Proteínas
12.
Hypertension ; 63(1): 68-73, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24126179

RESUMO

Hypertension remains the main risk factor for cardiovascular death. Environmental and biological factors are known to contribute to the condition, and circulating creatine kinase was reported to be the main predictor of blood pressure in the general population. This was proposed to be because of high resistance artery creatine kinase-BB rapidly regenerating ATP for vascular contractility. Therefore, we assessed whether creatine kinase isoenzyme mRNA levels in human resistance arteries are associated with blood pressure. We isolated resistance-sized arteries from omental fat donated by consecutive women undergoing uterine fibroid surgery. Blood pressure was measured in the sitting position. Vessels of 13 women were included, 6 normotensive and 7 hypertensive, mean age 42.9 years (SE, 1.6) and mean systolic/diastolic blood pressure, 144.8 (8.0)/86.5 (4.3) mm Hg. Arteriolar creatine kinase isoenzyme mRNA was assessed using quantitative real-time polymerase chain reaction. Normalized creatine kinase B mRNA copy numbers, ranging from 5.2 to 24.4 (mean, 15.0; SE, 1.9), showed a near-perfect correlation with diastolic blood pressure (correlation coefficient, 0.9; 95% confidence interval, 0.6-1.0) and were well correlated with systolic blood pressure, with a 90% relative increase in resistance artery creatine kinase B mRNA in hypertensives compared with normotensives, normalized copy numbers were, respectively, 19.3 (SE, 2.0) versus 10.1 (SE, 2.1), P=0.0045. To our knowledge, this is the first direct evidence suggesting that resistance artery creatine kinase mRNA expression levels concur with blood pressure levels, almost doubling with hypertension. These findings add to the evidence that creatine kinase might be involved in the vasculature's pressor responses.


Assuntos
Artérias/fisiopatologia , Pressão Sanguínea/fisiologia , Creatina Quinase/biossíntese , Hipertensão/fisiopatologia , Resistência Vascular/fisiologia , Adulto , Artérias/química , Artérias/metabolismo , Creatina Quinase/análise , Feminino , Expressão Gênica , Humanos , Hipertensão/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro
13.
PLoS One ; 8(7): e68991, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874842

RESUMO

OBJECTIVE: To systematically review the literature on human gene expression data of placental tissue in pre-eclampsia and to characterize a meta-signature of differentially expressed genes in order to identify novel putative diagnostic markers. DATA SOURCES: Medline through 11 February 2011 using MeSH terms and keywords related to placenta, gene expression and gene expression arrays; GEO database using the term "placent*"; and reference lists of eligible primary studies, without constraints. METHODS: From 1068 studies retrieved from the search, we included original publications that had performed gene expression array analyses of placental tissue in the third trimester and that reported on differentially expressed genes in pre-eclampsia versus normotensive controls. Two reviewers independently identified eligible studies, extracted descriptive and gene expression data and assessed study quality. Using a vote-counting method based on a comparative meta-profiling algorithm, we determined a meta-signature that characterizes the significant intersection of differentially expressed genes from the collection of independent gene signatures. RESULTS: We identified 33 eligible gene expression array studies of placental tissue in the 3(rd) trimester comprising 30 datasets on mRNA expression and 4 datasets on microRNA expression. The pre-eclamptic placental meta-signature consisted of 40 annotated gene transcripts and 17 microRNAs. At least half of the mRNA transcripts encode a protein that is secreted from the cell and could potentially serve as a biomarker. CONCLUSIONS: In addition to well-known and validated genes, we identified 14 transcripts not reported previously in relation to pre-eclampsia of which the majority is also expressed in the 1(st) trimester placenta, and three encode a secreted protein.


Assuntos
Perfilação da Expressão Gênica , Placenta/metabolismo , Pré-Eclâmpsia/genética , Feminino , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/patologia , Gravidez , Terceiro Trimestre da Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
14.
Reprod Sci ; 20(2): 190-201, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22593146

RESUMO

Preterm labor (PTL) is an important cause of preterm delivery. The trigger initiating the process toward overt labor and parturition is poorly understood and the molecular basis remains an enigma. It recently emerged that the overall occurrence of PTL in pregnant women with congenital heart disease (CHD) is increased. In this review, we present data on pregnancy in women with CHD and the opportunities this provides for research on the initiating mechanisms of inappropriately premature contractions. This may provide means for early detection of women at high risk of PTL in the general population, with models using cervical length, novel biomarkers, and maternal factors. We discuss human embryonic development of the heart and the uterus and the molecular pathways shared by the cardio- and uteromyocytes. We propose 2 hypotheses for the co-occurrence of maternal CHD and PTL; one based on a shared genetic origin and the other on a shared epigenetic origin.


Assuntos
Cardiopatias Congênitas/genética , Bem-Estar Materno , Trabalho de Parto Prematuro/genética , Nascimento Prematuro/genética , Animais , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/metabolismo , Humanos , Trabalho de Parto Prematuro/metabolismo , Gravidez , Nascimento Prematuro/metabolismo
15.
Pregnancy Hypertens ; 2(4): 358-67, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26105603

RESUMO

Pre-eclampsia, characterized by hypertension and proteinuria, affects approximately 3-5% of all pregnancies worldwide and is a major cause of maternal and fetal morbidity and mortality. Maternal endothelial dysfunction is associated with disease pathogenesis. Recently, reports have shown that elevated levels of circulating soluble fms-like tyrosine kinase 1 [sFlt1] and soluble endoglin [sEng] are associated with pre-eclampsia. Flt1 is a receptor for vascular endothelial growth factor receptor [VEGF], whereas endoglin [Eng] is an auxiliary receptor for transforming growth factor-ß [TGF-ß] super-family members. Both signaling pathways modulate angiogenesis and are involved in vascular homeostasis. Increased levels of sFlt1 and sEng dysregulate VEGF and TGF-ß signaling respectively, resulting in endothelial dysfunction of maternal blood vessels. This review summarizes our current knowledge of Flt1 and endoglin and soluble forms in pre-eclampsia. Furthermore, it highlights the predictive and early-screening value of circulating levels of sFlt1 and sEng for the risk of developing pre-eclampsia.

16.
PLoS One ; 6(4): e18303, 2011 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-21490965

RESUMO

BACKGROUND: Deregulation of platelet-derived growth factor (PDGF) signaling is a hallmark of malignant glioma. Two alternatively spliced PDGF-A mRNAs have been described, corresponding to a long (L) and a short (S) isoform of PDGF-A. In contrast to PDGF-A(S), the PDGF-A(L) isoform has a lysine and arginine rich carboxy-terminal extension that acts as an extracellular matrix retention motif. However, the exact role of PDGF-A(L) and how it functionally differs from the shorter isoform is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We overexpressed PDGF-A(L) as a transgene under control of the glial fibrillary acidic protein (GFAP) promoter in the mouse brain. This directs expression of the transgene to astrocytic cells and GFAP expressing neural stem cells throughout the developing and adult central nervous system. Transgenic mice exhibited a phenotype with enlarged skull at approximately 6-16 weeks of age and they died between 1.5 months and 2 years of age. We detected an increased number of undifferentiated cells in all areas of transgene expression, such as in the subependymal zone around the lateral ventricle and in the cerebellar medulla. The cells stained positive for Pdgfr-α, Olig2 and NG2 but this population did only partially overlap with cells positive for Gfap and the transgene reporter. Interestingly, a few mice presented with overt neoplastic glioma-like lesions composed of both Olig2 and Gfap positive cell populations and with microvascular proliferation, in a wild-type p53 background. CONCLUSIONS: Our findings show that PDGF-A(L) can induce accumulation of immature cells in the mouse brain. The strong expression of NG2, Pdgfr-α and Olig2 in PDGF-A(L) brains suggests that a fraction of these cells are oligodendrocyte progenitors. In addition, accumulation of fluid in the subarachnoid space and skull enlargement indicate that an increased intracranial pressure contributed to the observed lethality.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Glioma/metabolismo , Glioma/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Isoformas de Proteínas/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Proteína Glial Fibrilar Ácida , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos , Fator de Crescimento Derivado de Plaquetas/genética , Isoformas de Proteínas/genética , Fatores de Transcrição SOXB1/metabolismo
17.
Thyroid ; 20(7): 811-21, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20578903

RESUMO

BACKGROUND: Thyroid hormone is prerequisite for proper fetal and postnatal neurodevelopment, growth, and metabolism. Although much progress has been made in the characterization of genes implicated in thyroid development and function, the majority of genes involved in this process are still unknown. We have previously applied serial analysis of gene expression (SAGE) to identify novel genes preferentially expressed in the thyroid, and this has resulted in the characterization of DUOX2 and IYD (also known as DEHAL1), two genes encoding essential enzymes in the production of thyroid hormone. In the current study we characterize the gene C16orf89, which is linked to another thyroid-specific SAGE tag CCAGCTGCCT. METHODS: We establish tissue-specific expression of C16orf89 using novel tissue-specific SAGE libraries and quantitative polymerase chain reaction. In addition, we characterize the C16orf89 gene and protein, and analyze its mRNA expression in response to thyrotropin and during mouse development. RESULTS: C16orf89 is predominantly expressed in human thyroid tissue with a specificity intermediate between thyroid transcription factors and proteins involved in thyroid hormone synthesis. C16orf89 shows the same expression pattern as Nkx2-1 (thyroid transcription factor 1) from embryonic day (E) 17.5 onward in the developing mouse thyroid and lung. The developmental timing of C16orf89 mRNA expression is similar to that of the iodide transporter Slc5a5 (also known as Nis). Both transcripts are detected from E17.5 in the developing thyroid. This is clearly later than the onset of Tg mRNA expression (from E14.5), while Nkx2-1 and Iyd mRNA can already be detected in the E12.5 thyroid. In in vitro cell culture C16orf89 expression is stimulated by thyrotropin. The major splice variant encodes a 361 amino acid protein that is well conserved between mammals, contains an N-terminal signal peptide, is secreted in a glycosylated form, and does not contain any known functional domain. CONCLUSIONS: We present a novel gene highly expressed in thyroid that encodes a currently enigmatic protein.


Assuntos
Glicoproteínas/química , Glicoproteínas/genética , Glândula Tireoide/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Células Cultivadas , Cromossomos Humanos Par 16/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/metabolismo , Glicosilação , Humanos , Camundongos , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Fases de Leitura Aberta/genética , Especificidade de Órgãos , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Sinais Direcionadores de Proteínas , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Ratos , Análise de Sequência de RNA , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/embriologia , Glândula Tireoide/patologia , Tireotropina/farmacologia
18.
Glia ; 57(11): 1143-53, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19115382

RESUMO

Glioblastomas are the most common and malignant astrocytic brain tumors in human adults. The tumor suppressor gene TP53 is commonly mutated and/or lost in astrocytic brain tumors and the TP53 alterations are often found in combination with excessive growth factor signaling via PDGF/PDGFRalpha. Here, we have generated transgenic mice over-expressing human PDGFB in brain, under control of the human GFAP promoter. These mice showed no phenotype, but on a Trp53 null background a majority of them developed brain tumors. This occurred at 2-6 months of age and tumors displayed human glioblastoma-like features with integrated development of Pdgfralpha+ tumor cells and Pdgfrbeta+/Nestin+ vasculature. The transgene was expressed in subependymal astrocytic cells, in glia limitans, and in astrocytes throughout the brain substance, and subsequently, microscopic tumor lesions were initiated equally in all these areas. With tumor size, there was an increase in Nestin positivity and variability in lineage markers. These results indicate an unexpected plasticity of all astrocytic cells in the adult brain, not only of SVZ cells. The results also indicate a contribution of widely distributed Pdgfralpha+ precursor cells in the tumorigenic process.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Genes p53 , Proteína Glial Fibrilar Ácida/genética , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-sis/metabolismo , Animais , Astrócitos/metabolismo , Encéfalo/irrigação sanguínea , Neoplasias Encefálicas/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/metabolismo , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neuroglia/metabolismo , Proteínas Proto-Oncogênicas c-sis/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo
19.
Int J Cancer ; 123(2): 322-329, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18464291

RESUMO

Aberrant expression of the platelet-derived growth factor alpha-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2alpha, H2beta, H2gamma and H2delta. Of these haplotypes H1 and H2alpha are the most common, whereby H1 drives low and H2alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.


Assuntos
Glioblastoma/química , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Acetilação , Adulto , Idoso , Estudos de Casos e Controles , Metilação de DNA , Eletroforese em Gel de Poliacrilamida , Europa (Continente)/epidemiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Glioblastoma/epidemiologia , Glioblastoma/genética , Haplótipos , Histonas/metabolismo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Fatores de Risco , Regulação para Cima
20.
Differentiation ; 73(2-3): 109-19, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15811134

RESUMO

Pdgfra is expressed in the mesenchyme of multiple organs during embryonic development and Pdgfralpha is involved in cell proliferation, differentiation, migration, and apoptosis in many tissues. A fine-tuned regulation of gene transcription is required to achieve these effects. To investigate if the Shh signaling pathway is involved in the tightly regulated Pdgfra expression during embryogenesis, we systematically compared Gli1 and Pdgfralpha mRNA expression patterns in vivo from mouse embryonic day 9.5 to 14.5. We found that an initial partly overlapping expression of Gli1 and Pdgfralpha in the mesenchyme of foregut and somites was changed to different expression patterns when the mesenchyme differentiated into specialized structures such as intestinal villi and chondrocytes. Gli1 and Pdgfra were also expressed differently in the developing lung, heart, central nervous system, skin, tooth, and eye. Importantly, neither Pdgfralpha mRNA patterns nor levels were altered in Ihh mutant embryos although Gli1 and Ptc mRNA levels were dramatically reduced. Our results demonstrate that Gli1 is not required to induce Pdgfra expression during embryonic bone development, and are consistent with previous findings that Pdgfralpha and Hh pathways serve different functions in, e.g., bone, gut, and lung development. However, we cannot exclude the possibility that Glis can have more complex regulatory effects on Pdgfra gene activity, nor can we exclude such effects in pathological conditions.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Sítios de Ligação , Sequência Conservada , Desenvolvimento Embrionário/genética , Fatores de Transcrição Kruppel-Like , Camundongos , Camundongos Endogâmicos , Mutagênese , RNA Mensageiro/genética , Proteína GLI1 em Dedos de Zinco
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