Gestational Diabetes Induces Placental Genes for Chronic Stress and Inflammatory Pathways

Department of Reproductive Biology, Schwartz Center for Metabolism and Nutrition, University School of Medicine at MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
Diabetes (Impact Factor: 8.1). 01/2004; 52(12):2951-8. DOI: 10.2337/diabetes.52.12.2951
Source: PubMed


A physiological state of insulin resistance is required to preferentially direct maternal nutrients toward the feto-placental unit, allowing adequate growth of the fetus. When women develop gestational diabetes mellitus (GDM), insulin resistance is more severe and disrupts the intrauterine milieu, resulting in accelerated fetal development with increased risk of macrosomia. As a natural interface between mother and fetus, the placenta is the obligatory target of such environmental changes. However, the molecular basis for the imbalance that leads to fetal, neonatal, and adult metabolic compromises is not well understood. We report that GDM elicits major changes in the expression profile of placental genes with a prominent increase in markers and mediators of inflammation. Within the 435 transcripts reproducibly modified, genes for stress-activated and inflammatory responses represented the largest functional cluster (18.5% of regulated genes). Upregulation of interleukins, leptin, and tumor necrosis factor-alpha receptors and their downstream molecular adaptors indicated an activation of pathways recruiting stress-activated protein/c-Jun NH(2)-terminal kinases. Transcriptional activation of extracellular matrix components and angiogenic activators pointed to a major structural reorganization of the placenta. Thus, placental transcriptome emerges as a primary target of the altered environment of diabetic pregnancy. The genes identified provide the basis to elucidate links between inflammatory pathways and GDM-associated insulin resistance.

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Available from: Patrick M Catalano, Aug 30, 2015
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    • "In GDM, placental transcriptome analysis has shown the activation of multiple signal transduction pathways, involving inflammatory mediators, such as TNF-α, IL-1 and leptin, which may contribute to cell hypertrophy and a dysfunctional vasculosyncytial membrane (Radaelli et al., 2003). These results suggest that the fetus of diabetic mothers develops in an inflammatory milieu. "
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    ABSTRACT: Hyperglycemic memory describes the progression of diabetic complications during subsequent periods of improved glycemia.We addressed the hypothesis that transient hyperglycemia causes aberrant cyclooxygenase(COX)-2 expression in human umbilical vein endothelial cells(HUVEC) in response to interleukin(IL)-1β through the induction of long-lasting epigenetic changes involving microRNA-16(miR-16), a post-transcriptional modulator of COX-2 expression. Studies were performed in HUVEC collected from gestational diabetes mellitus(GDM)(dHUVEC) and normal women(nHUVEC). In dHUVEC treated with IL-1β, we found enhanced expression of COX-2 mRNA and protein and increased generation of prostanoids[the most abundant was the promitogenic prostaglandin(PG)F2α ]. COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 downregulation and c-Myc induction(a repressor of miR expression). dHUVEC showed higher cellular proliferation in response to IL-1β which was abrogated by COX-2 inhibition and PGF2α receptor antagonism. Comparable changes of COX-2 mRNA, miR-16 and c-Myc detected in dHUVEC were produced in nHUVEC exposed to transient high glucose and then stimulated with IL-1β under physiological glucose levels. Under these experimental conditions, enhanced superoxide anion production was detected. Our results describe a possible mechanism operating in GDM that links enhanced superoxide anion production and epigenetic changes, associated with hyperglycemic memory, to endothelial dysfunction through dysregulated post-transcriptional control of COX-2 gene expression in response to inflammatory stimuli. The association of conventional therapy for glycemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of GDM complications. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 07/2015; DOI:10.1111/bph.13241 · 4.84 Impact Factor
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    • "Expression of both IL6 and TNFA is sensitive to oxidative stress. Indeed, hyperglycemia stimulates expression of IL6 in trophoblasts [118] and placental expression of IL6 and TNFA is increased [113, 119, 120], but their levels in the fetal circulation are unchanged or even reduced [121, 122]. Thus, TNFA and IL6 may affect placental angiogenesis locally, that is, in a paracrine manner. "
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    ABSTRACT: The placental vasculature rapidly expands during the course of pregnancy in order to sustain the growing needs of the fetus. Angiogenesis and vascular growth are stimulated and regulated by a variety of growth factors expressed in the placenta or present in the fetal circulation. Like in tumors, hypoxia is a major regulator of angiogenesis because of its ability to stimulate expression of various proangiogenic factors. Chronic fetal hypoxia is often found in pregnancies complicated by maternal diabetes as a result of fetal hyperglycaemia and hyperinsulinemia. Both are associated with altered levels of hormones, growth factors, and proinflammatory cytokines, which may act in a proangiogenic manner and, hence, affect placental angiogenesis and vascular development. Indeed, the placenta in diabetes is characterized by hypervascularisation, demonstrating high placental plasticity in response to diabetic metabolic derangements. This review describes the major regulators of placental angiogenesis and how the diabetic environment in utero alters their expression. In the light of hypervascularized diabetic placenta, the focus was placed on proangiogenic factors.
    BioMed Research International 09/2014; 2014:145846. DOI:10.1155/2014/145846 · 2.71 Impact Factor
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    • "However, no studies have focused on the effects of hyperglycemia on HBCs. Some studies have demonstrated that diabetes, during pregnancy, alters the expression of placental genes related to markers and mediators of inflammation and leads to impaired fetal growth and programming, which causes several metabolic diseases [16]. The goal of our study was to investigate the direct effects of hyperglycemia on HBCs through in vivo and in vitro systems. "
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    ABSTRACT: Growing evidence indicates that maternal pathophysiological conditions, such as diabetes, influence fetal growth and could program metabolic disease in adulthood. Placental cells, particularly Hofbauer cells (HBCs), which are placental macrophages characterized by an anti-inflammatory profile (M2), can sense the modified maternal environment. The goal of this study was to investigate the direct effect of hyperglycemia on HBCs. We studied, at mRNA and protein levels, some markers of M2 and M1 (pro-inflammatory) macrophages in placentae from control and diabetic patients to assess the balance between pro- and anti-inflammatory macrophages: an imbalance of M2 to M1 macrophages has been observed in humans. We used pregnant rats, receiving a single injection of streptozotocin (STZ), as a model of maternal diabetes. We noticed a M2-to-M1 macrophage unbalance as we observed in human. An in vitro model of isolated rat HBCs was used to identify the direct effects of high glucose. We found that high glucose stimulation activated genes belonging to TLR (Toll-Like Receptor)-dependent inflammatory pathways. Moreover, the HBCs stimulated by high glucose switched their M2 profile towards M1, with increased expression of pro-inflammatory cytokines and markers. We also noticed that the oxidative-stress pathway was activated in response to high glucose driven by Hif-1α. In this study, we demonstrated that diabetes/hyperglycemia affect the anti-inflammatory profile of HBCs, by stimulating these cells to acquire an inflammatory profile leading adverse consequences for the fetal-placental-maternal axis.
    Biochimica et Biophysica Acta 07/2013; 1832(12). DOI:10.1016/j.bbadis.2013.07.009 · 4.66 Impact Factor
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