The effect of gestational age on angiogenic gene expression in the rat placenta (original) (raw)
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BMC Pregnancy and Childbirth, 2009
Background: Preterm delivery (PTD) is a significant public health problem associated with greater risk of mortality and morbidity in infants and mothers. Pathophysiologic processes that may lead to PTD start early in pregnancy. We investigated early pregnancy peripheral blood global gene expression and PTD risk. Methods: As part of a prospective study, ribonucleic acid was extracted from blood samples (collected at 16 weeks gestational age) from 14 women who had PTD (cases) and 16 women who delivered at term (controls). Gene expressions were measured using the GeneChip ® Human Genome U133 Plus 2.0 Array. Student's T-test and fold change analysis were used to identify differentially expressed genes. We used hierarchical clustering and principle components analysis to characterize signature gene expression patterns among cases and controls. Pathway and promoter sequence analyses were used to investigate functions and functional relationships as well as regulatory regions of differentially expressed genes. Results: A total of 209 genes, including potential candidate genes (e.g. PTGDS, prostaglandin D2 synthase 21 kDa), were differentially expressed. A set of these genes achieved accurate prediagnostic separation of cases and controls. These genes participate in functions related to immune system and inflammation, organ development, metabolism (lipid, carbohydrate and amino acid) and cell signaling. Binding sites of putative transcription factors such as EGR1 (early growth response 1), TFAP2A (transcription factor AP2A), Sp1 (specificity protein 1) and Sp3 (specificity protein 3) were over represented in promoter regions of differentially expressed genes. Real-time PCR confirmed microarray expression measurements of selected genes. Conclusions: PTD is associated with maternal early pregnancy peripheral blood gene expression changes. Maternal early pregnancy peripheral blood gene expression patterns may be useful for better understanding of PTD pathophysiology and PTD risk prediction.
Prenatal Diagnosis, 2008
ObjectiveTo evaluate the direct alterations in mRNA expression among chorionic villous samples from 11 weeks' pregnant women who would develop preeclampsia (PE) later in the pregnancy.To evaluate the direct alterations in mRNA expression among chorionic villous samples from 11 weeks' pregnant women who would develop preeclampsia (PE) later in the pregnancy.MethodCase-control study encompassing five women destined to develop PE [cases matched 1:5 for gestational age (GA) with 25 controls]. We quantified mRNA expression on tissue samples from chorionic villous sampling (CVS) of normal and PE patients. We then assessed mRNA expressions of vascular endothelial growth factor (VEGFA), VEGFA receptor 1 (Flt-1), endoglin (Eng), placental growth factor (PlGF), transforming growth factor-β1 (TGF-β1), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD). Data were analyzed by nonparametric rank analysis.Case-control study encompassing five women destined to develop PE [cases matched 1:5 for gestational age (GA) with 25 controls]. We quantified mRNA expression on tissue samples from chorionic villous sampling (CVS) of normal and PE patients. We then assessed mRNA expressions of vascular endothelial growth factor (VEGFA), VEGFA receptor 1 (Flt-1), endoglin (Eng), placental growth factor (PlGF), transforming growth factor-β1 (TGF-β1), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD). Data were analyzed by nonparametric rank analysis.ResultsFor all the mRNA species considered in this study, all the mean observed ranks in the PE group were significantly altered compared to the rank expectation among controls. mRNA for Eng and TGF-β1 were the markers with the highest degree of aberration in PE, in respect to controls. The results are consistent with those already reported for the corresponding circulating proteins. mRNA for HO-1 and SOD were instead associated with the lowest aberration.For all the mRNA species considered in this study, all the mean observed ranks in the PE group were significantly altered compared to the rank expectation among controls. mRNA for Eng and TGF-β1 were the markers with the highest degree of aberration in PE, in respect to controls. The results are consistent with those already reported for the corresponding circulating proteins. mRNA for HO-1 and SOD were instead associated with the lowest aberration.ConclusionIt is assumed that the pathogenesis of PE is associated with pathophysiological alterations to trophoblasts in early gestation. Our study has directly proved that gene expressions relating to angiogenesis or oxidative stress are altered in the first trimester trophoblasts that go on to develop PE later. These results would put the basis for a possible screening method for PE by using residual CVS. Copyright © 2008 John Wiley & Sons, Ltd.It is assumed that the pathogenesis of PE is associated with pathophysiological alterations to trophoblasts in early gestation. Our study has directly proved that gene expressions relating to angiogenesis or oxidative stress are altered in the first trimester trophoblasts that go on to develop PE later. These results would put the basis for a possible screening method for PE by using residual CVS. Copyright © 2008 John Wiley & Sons, Ltd.
Mid-to-Late Gestational Changes in Inflammatory Gene Expression in the Rat Placenta
Reproductive Sciences, 2017
Background: The placenta plays an important role during pregnancy providing maternal blood supply from the uterus to the developing fetus. The structure and function of the placenta changes with gestation, as the fetus develops and its demands change. This study aims to elucidate changes in cytokine and chemokine gene expression throughout mid-to-late gestation in rat placenta. Methods: Sprague Dawley rats were time-mated, and placentae were obtained from 6 pregnant dams at 4 different gestational periods: E14.25, E15.25, E17.25, and E20. Changes in placental gene expression were measured by microarray analysis. Differentially expressed inflammatory genes were functionally categorized by pathway analysis. To validate the microarray results, a subset of genes was analyzed by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort of 22 rats. Results: Changes in messenger RNA (mRNA) expression of various cytokines, chemokines, and genes of the tumor growth factor b and tumor necrosis factor family were analyzed in rat placentae at E14.25, E15.25, E17.25, and E20. Forty-six genes were differentially expressed, and of these 21 genes had increased expression in late gestation (E20). The gestational age pattern of gene expression was confirmed by qPCR in the validation cohort. Conclusion: The observed acute, prelabor changes in the expression of these genes during gestation warrant further investigation to elucidate their role in pregnancy and parturition.
Altered gene expression in human placenta after suspected preterm labour
Placenta, 2017
Introduction: Suspected preterm labour occurs in around 9% of pregnancies. However, almost two-thirds of women admitted for threatened preterm labour ultimately deliver at term and are considered risk-free for fetal development. Methods: We examined placental and umbilical cord blood samples from preterm or term deliveries after threatened preterm labour as well as term deliveries without threatened preterm labour. We quantitatively analysed the mRNA expression of inflammatory markers (IL6, IFNγ, and TNFα) and modulators of angiogenesis (FGF2, PGF, VEGFA, VEGFB, and VEGFR1). Results: A total of 132 deliveries were analysed. Placental samples from preterm and term deliveries after suspected preterm labour exhibited significantly increased expression of TNFα and IL6 and decreased expression of IFNγ. Suspected preterm labour was also associated with altered expression of angiogenic factors, although not all differences reached statistical significance. Discussion: We found gene expression patterns indicative of inflammation in human placentas after suspected preterm labour regardless of whether the deliveries occurred preterm or at term. Similarly, a trend towards altered expression of angiogeneic factors was not limited to preterm birth. These findings suggest that the biological mechanisms underlying threatened preterm labour affect pregnancies independently of gestational age at birth.
Global Gene Expression Changes Induced in the Human Placenta during Labor
Placenta, 2010
Objectives: To gain insight into the process of labor and the effects of labor on placental gene expression, we performed a microarray analysis to identify the differentially expressed transcripts that may participate in labor onset and progression. Methods: We compared expression profiles in placentas from 16 women who underwent elective nonlabored cesarean section and from seven women who underwent vaginal delivery. Oligonucleotide probes representing 55,000 genes were used to measure gene expression. Differential gene expression was evaluated using the Student's t-test and fold change assessment and reverse transcription PCR was used to validate the differentially expressed genes. Results: A total of 351 genes were found to be differentially expressed between the two groups. Among these differentially expressed genes, 344 genes were up-regulated and seven were down-regulated. These differentially expressed genes involved 15 categories including genes involved in stress response, immune response, cell death, coagulation, and blood vessel development which are considered to be most closely associated with the inflammatory response that characterizes labor. Conclusion: A total of 351 differentially expressed genes of 15 categories were found in the placentas of the vaginal delivery group, indicating a diversity of gene expression alteration and complexity in the labor process. These gene expression changes could be a cause of labor onset and progress or simply an effect of labor.
Gene expression patterns in human placenta
Proceedings of the National Academy of Sciences, 2006
The placenta is the principal metabolic, respiratory, excretory, and endocrine organ for the first 9 months of fetal life. Its role in fetal and maternal physiology is remarkably diverse. Because of the central role that the placenta has in fetal and maternal physiology and development, the possibility that variation in placental gene expression patterns might be linked to important abnormalities in maternal or fetal health, or even variations in later life, warrants investigation. As an initial step, we used DNA microarrays to analyze gene expression patterns in 72 samples of amnion, chorion, umbilical cord, and sections of villus parenchyma from 19 human placentas from successful full-term pregnancies. The umbilical cord, chorion, amnion, and villus parenchyma samples were readily distinguished by differences in their global gene-expression patterns, many of which seemed to be related to physiology and histology. Differentially expressed genes have roles that include placental trophoblast secretion, signal transduction, metabolism, immune regulation, cell adhesion, and structure. We found interindividual differences in expression patterns in villus parenchyma and systematic differences between the maternal, fetal, and intermediate layers. A group of genes that was expressed in both the maternal and fetal villus parenchyma sections of placenta included genes that may be associated with preeclampsia. We identified sets of genes whose expression in placenta was significantly correlated with the sex of the fetus. This study provides a rich and diverse picture of the molecular variation in the placenta from healthy pregnancies. microarray ͉ pregnancy ͉ transcriptome ͉ preeclampsia Conflict of interest statement: No conflicts declared. This paper was submitted directly (Track II) to the PNAS office. Freely available online through the PNAS open access option.
Differential placental gene expression in preeclampsia
American Journal of Obstetrics and Gynecology, 2008
Objective-Candidate genes associated with preeclampsia have not been fully described. We conducted microarray and confirmatory QRT-PCR studies to investigate global placental gene expression in preeclampsia. Study design-RNA was extracted from placental samples collected from 18 preeclampsia cases and 18 normotensive controls. Oligonucleotide probes representing 22,000 genes were used to measure gene expression in each sample. Differential gene expression was evaluated using Students T-test, fold change assessment and Significance Analysis of Microarrays (SAM). Functions and functional relationships of differentially expressed genes were evaluated. Results-Genes (n=58) participating in immune system, inflammation, oxidative stress, signaling, growth and development pathways were differentially expressed in preeclampsia. These genes include previously described candidate genes (such as LEP), potential candidate genes with related functions (such as CYP11A) and novel genes (such as CDKN1C). Conclusion-Expression of genes (both candidate and novel) with diverse functions is associated with preeclampsia risk, reflecting the complex pathogenesis.
Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies
Molecular Human Reproduction, 2006
The aim of this study was to investigate patterns of gene expression in placental samples from patients with preeclampsia (PE), persistent bilateral uterine artery notching (without PE), and normal controls. This study included placental tissue from nine women with PE, seven with uncomplicated pregnancies and five with bilateral uterine artery notching in Doppler velocimetry tracings. Human cDNA microarrays with 6500 transcripts/genes were used and the results verified with real-time PCR and in-situ hybridization. Multidimensional scaling method and random permutation technique demonstrated significant differences among the three groups examined. Within the 6.5K arrays, 6198 elements were unique cDNA clones representing 5952 unique UniGenes and 5695 unique LocusLinks. Multidimensional scaling plots showed 5000 genes that met our quality criteria; among these, 366 genes were significantly different in at least one comparison.
Gene expression profiling of pre-eclamptic placentae by RNA sequencing
Scientific Reports, 2015
Pre-eclampsia is a common and complex pregnancy disorder that often involves impaired placental development. In order to identify altered gene expression in pre-eclamptic placenta, we sequenced placental transcriptomes of nine pre-eclamptic and nine healthy pregnant women in pools of three. The differential gene expression was tested both by including all the pools in the analysis and by excluding some of the pools based on phenotypic characteristics. From these analyses, we identified altogether 53 differently expressed genes, a subset of which was validated by qPCR in 20 cases and 19 controls. Furthermore, we conducted pathway and functional analyses which revealed disturbed vascular function and immunological balance in pre-eclamptic placenta. Some of the genes identified in our study have been reported by numerous microarray studies (BHLHE40, FSTL3, HK2, HTRA4, LEP, PVRL4, SASH1, SIGLEC6), but many have been implicated in only few studies or have not previously been linked to pr...
Gene expression profile in labouring and non-labouring human placenta near term
Molecular Human Reproduction, 2008
The duration of pregnancy and initiation of labour are thought to be controlled by fetal, maternal and placental factors. The aim of this study was to investigate whether labour influences gene expression in placenta near term. Placental samples were obtained from 27 women after vaginal delivery (labouring) and 17 women after elective Caesarean section (non-labouring). All women were Caucasian and