Article

Altered Global Gene Expression in First Trimester Placentas of Women Destined to Develop Preeclampsia

School of Nursing, Department of Health Promotion and Development, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Placenta (Impact Factor: 3.29). 12/2008; 30(1):15-24. DOI: 10.1016/j.placenta.2008.09.015
Source: PubMed

ABSTRACT Preeclampsia is a pregnancy-specific disorder that remains a leading cause of maternal, fetal and neonatal morbidity and mortality, and is associated with risk for future cardiovascular disease. There are no reliable predictors, specific preventative measures or treatments other than delivery. A widely held view is that the antecedents of preeclampsia lie with impaired placentation in early pregnancy. Accordingly, we hypothesized dysregulation of global gene expression in first trimester placentas of women who later manifested preeclampsia.
Surplus chorionic villus sampling (CVS) tissues were collected at 10-12 weeks gestation in 160 patients with singleton fetuses. Four patients developed preeclampsia, and their banked CVS specimens were matched to 8 control samples from patients with unaffected pregnancies. Affymetrix HG-U133 Plus 2.0 GeneChips were utilized for microarray analysis. Naïve Bayes prediction modeling and pathway analysis were conducted. qRT-PCR examined three of the dysregulated genes.
Thirty-six differentially expressed genes were identified in the preeclampsia placentas. qRT-PCR verified the microarray analysis. Thirty-one genes were down-regulated. Many were related to inflammation/immunoregulation and cell motility. Decidual gene dysregulation was prominent. No evidence was found for alterations in hypoxia and oxidative stress regulated genes.
To our knowledge, this is the first study to show dysregulation of gene expression in the early placentas of women approximately 6 months before developing preeclampsia, thereby reinforcing a placental origin of the disorder. We hypothesize that placentation in preeclampsia is compromised in the first trimester by maternal and fetal immune dysregulation, abnormal decidualization, or both, thereby impairing trophoblast invasion. Several of the genes provide potential targets for the development of clinical biomarkers in maternal blood during the first trimester. Supplementary materials are available for this article via the publisher's online edition.

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Available from: William Allen Hogge, Aug 05, 2015
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    • "Whilst the clinical manifestations of pre-eclampsia occur in late pregnancy, the molecular events leading into the onset of this disease are thought to originate in early pregnancy [1]. In support of this, global alterations in the expression of genes related to inflammation/immunoregulation and cell motility were found in the placenta of first trimester women that subsequently developed pre-eclampsia [4], which has re-enforced the concept of a placental origin of the disorder. As a result, it is generally accepted that pre-eclampsia occurs secondary to insufficient placentation (development of the placenta) [5] [6]. "
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    ABSTRACT: Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-β superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Cytokine 02/2015; 71(2). DOI:10.1016/j.cyto.2014.11.017 · 2.87 Impact Factor
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    • "Whilst the clinical manifestations of pre-eclampsia occur in late pregnancy, the molecular events leading into the onset of this disease are thought to originate in early pregnancy [1]. In support of this, global alterations in the expression of genes related to inflammation/immunoregulation and cell motility were found in the placenta of first trimester women that subsequently developed pre-eclampsia [4], which has re-enforced the concept of a placental origin of the disorder. As a result, it is generally accepted that pre-eclampsia occurs secondary to insufficient placentation (development of the placenta) [5] [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-b superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro-inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function.
    Cytokine 12/2014; · 2.87 Impact Factor
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    • "Among these collagen receptors only the integrin heterodimers a 1 b 1 and a 2 b 1 and soluble receptor LAIR-2 are known to be expressed by trophoblast [20e22]. LAIR-2 is exclusively expressed by invading trophoblast cells and is significantly down-regulated in chorionic villous samples from women who subsequently develop preeclampsia [23] [24]. Integrins alpha 10 (a10) and alpha 11 (a11) and collagen receptors DDR-1 and DDR-2 that also bind to col-IV and fibril-forming collagens are linked with the progression of various tumours via mediating cell migration [25e28]. "
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    ABSTRACT: Introduction Extracellular matrix proteins play a crucial role in influencing the invasion of trophoblast cells. However the role of collagens and collagen type IV (col-IV) in particular at the implantation site is not clear. Methods Immunohistochemistry was used to determine the distribution of collagen types I, III, IV and VI in endometrium and decidua during the menstrual cycle and the first trimester of pregnancy. Expression of col-IV alpha chains during the reproductive cycle was determined by qPCR and protein localisation by immunohistochemistry. The structure of col-IV in placenta was examined using transmission electron microscopy. Finally, the expression of col-IV alpha chain NC1 domains and collagen receptors was localised by immunohistochemistry. Results Col-IV alpha chains were selectively up-regulated during the menstrual cycle and decidualisation. Primary extravillous trophoblast cells express collagen receptors and secrete col-IV in vitro and in vivo, resulting in the increased levels found in decidua basalis compared to decidua parietalis. A novel expression pattern of col-IV in the mesenchyme of placental villi, as a three-dimensional network, was found. NC1 domains of col-IV alpha chains are known to regulate tumour cell migration and the selective expression of these domains in decidua basalis compared to decidua parietalis was determined. Discussion Col-IV is expressed as novel forms in the placenta. These findings suggest that col-IV not only represents a structural protein providing tissue integrity but also influences the invasive behaviour of trophoblast cells at the implantation site.
    Placenta 11/2014; 36(1). DOI:10.1016/j.placenta.2014.10.012 · 3.29 Impact Factor
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