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1.
Artigo em Inglês | MEDLINE | ID: mdl-31913647

RESUMO

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF-1) is important in growth, differentiation and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for two persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex-specific. The PSE effect was less pronounced in adult offspring compared to the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared to the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when combining the data of all three stages. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming which supports the developmental origins of health and disease (DOHaD) hypothesis.

2.
Biochim Biophys Acta Mol Basis Dis ; 1866(2): 165397, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30699363

RESUMO

Gestational diabetes mellitus (GDM) is a detrimental condition for human pregnancy associated with endothelial dysfunction and endothelial inflammation in the fetoplacental vasculature and leads to increased cardio-metabolic risk in the offspring. In the fetoplacental vasculature, GDM is associated with altered adenosine metabolism. Adenosine is an important vasoactive molecule and is an intermediary and final product of transmethylation reactions in the cell. Adenosine kinase is the major regulator of adenosine levels. Disruption of this enzyme is associated with alterations in methylation-dependent gene expression regulation mechanisms, which are associated with the fetal programming phenomenon. Here we propose that cellular and molecular alterations associated with GDM can dysregulate adenosine kinase leading to fetal programming in the fetoplacental vasculature. This can contribute to the cardio-metabolic long-term consequences observed in offspring after exposure to GDM.

3.
Redox Biol ; 28: 101329, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31550664

RESUMO

Pregnancy complications such as preeclampsia cause increased fetal oxidative stress and fetal growth restriction, and associate with a higher incidence of adult metabolic syndrome. However, the pathophysiological contribution of oxidative stress per se is experimentally difficult to discern and has not been investigated. This study determined, if increased intrauterine oxidative stress (IUOx) affects adiposity, glucose and cholesterol metabolism in adult Ldlr-/-xSod2+/+ offspring from crossing male Ldlr-/-xSod2+/+ mice with Ldlr-/-xSod2 +/- dams (IUOx) or Ldlr-/-xSod2 +/- males with Ldlr-/-xSod2+/+ dams (control). At 12 weeks of age mice received Western diet for an additional 12 weeks. Adult male IUOx offspring displayed lower body weight and reduced adiposity associated with improved glucose tolerance compared to controls. Reduced weight gain in IUOx was conceivably due to increased energy dissipation in white adipose tissue conveyed by higher expression of Ucp1 and an accompanying decrease in DNA methylation in the Ucp1 enhancer region. Female offspring did not show comparable phenotypes. These results demonstrate that fetal oxidative stress protects against the obesogenic effects of Western diet in adulthood by programming energy dissipation in white adipose tissue at the level of Ucp1.

4.
Am J Obstet Gynecol ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31836544

RESUMO

BACKGROUND: Preeclampsia is a hypertensive pregnancy disorder in which generalized systemic inflammation and maternal endothelial dysfunction are involved in the pathophysiology. MiRNAs are small noncoding RNAs responsible for post-transcriptional regulation of gene expression and involved in many physiological processes. They mainly downregulate translation of their target genes. OBJECTIVE: We aimed to compare the plasma miRNA concentrations in preeclampsia, healthy pregnant women, and nonpregnant women. Furthermore, we aimed to evaluate the effect of 3 highly increased plasma miRNAs in preeclampsia on endothelial cell function in vitro. STUDY DESIGN: We compared 3391 (precursor) miRNA concentrations in plasma samples from early-onset preeclamptic women, gestational age-matched healthy pregnant women, and nonpregnant women using miRNA 3.1. arrays (Affymetrix) and validated our findings by real-time quantitative polymerase chain reaction. Subsequently, endothelial cells (human umbilical vein endothelial cells) were transfected with microRNA mimics (we choose the 3 miRNAs with the greatest fold change and lowest false-discovery rate in preeclampsia vs healthy pregnancy). After transfection, functional assays were performed to evaluate whether overexpression of the microRNAs in endothelial cells affected endothelial cell function in vitro. Functional assays were the wound-healing assay (which measures cell migration and proliferation), the proliferation assay, and the tube-formation assay (which assesses formation of endothelial cell tubes during the angiogenic process). To determine whether the miRNAs are able to decrease gene expression of certain genes, RNA was isolated from transfected endothelial cells and gene expression (by measuring RNA expression) was evaluated by gene expression microarray (Genechip Human Gene 2.1 ST arrays; Life Technologies). For the microarray, we used pooled samples, but the differently expressed genes in the microarray were validated by real-time quantitative polymerase chain reaction in individual samples. RESULTS: No significant differences (fold change <-1.2 or >1.2 with a false-discovery rate <0.05) were found in miRNA plasma concentrations between healthy pregnant and nonpregnant women. The plasma concentrations of 26 (precursor) miRNAs were different between preeclampsia and healthy pregnancy. The 3 miRNAs that were increased with the greatest fold change and lowest false-discovery rate in preeclampsia vs healthy pregnancy were miR-574-5p, miR-1972, and miR-4793-3p. Transfection of endothelial cells with these miRNAs in showed that miR-574-5p decreased (P<.05) the wound-healing capacity (ie, decreased endothelial cell migration and/or proliferation) and tended (P<.1) to decrease proliferation, miR-1972 decreased tube formation (P<.05), and also tended (P<.1) to decrease proliferation, and miR-4793-3p tended (P<.1) to decrease both the wound-healing capacity and tube formation in vitro. Gene expression analysis of transfected endothelial cells revealed that miR-574-5p tended (P<.1) to decrease the expression of the proliferation marker MKI67. CONCLUSION: We conclude that in the early-onset preeclampsia group in our study different concentrations of plasma miRNAs are present as compared with healthy pregnancy. Our results suggest that miR-574-5p and miR-1972 decrease the proliferation (probably via decreasing MKI67) and/or migration as well as the tube-formation capacity of endothelial cells. Therefore, these miRNAs may be antiangiogenic factors affecting endothelial cells in preeclampsia.

5.
PLoS One ; 14(8): e0221972, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31469872

RESUMO

BACKGROUND: In Fetal Growth Restriction 'fetal programming' may take place via DNA methylation, which has implications for short-term and long-term health outcomes. Small-for-gestational age fetuses are considered fetal growth restricted, characterized by brain-sparing when fetal Doppler hemodynamics are abnormal, expressed as a cerebroplacental ratio (CPR) <1. We aimed to determine whether brain-sparing is associated with altered DNA methylation of selected genes. METHODS: We compared DNA methylation of six genes in 41 small-for-gestational age placentas with a normal or abnormal CPR. We selected EPO, HIF1A, VEGFA, LEP, PHLDA2, and DHCR24 for their role in angiogenesis, immunomodulation, and placental and fetal growth. DNA methylation was analyzed by pyrosequencing. RESULTS: Growth restricted fetuses with an abnormal CPR showed hypermethylation of the VEGFA gene at one CpG (VEGFA-309, p = .001) and an overall hypomethylation of the LEP gene, being significant at two CpGs (LEP-123, p = .049; LEP-51, p = .020). No differences in methylation were observed for the other genes. CONCLUSIONS: VEGFA and LEP genes are differentially methylated in placentas of small-for-gestational age fetuses with brain-sparing. Hypermethylation of VEGFA-309 in abnormal CPR-placentas could indicate successful compensatory mechanisms. Methylation of LEP-51 is known to suppress LEP expression. Hypomethylation in small-for-gestational age placentas with abnormal CPR may result in hyperleptinemia and predispose to leptin-resistance later in life.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31105647

RESUMO

Objective: Management of late fetal growth restriction (FGR) is limited to adequate fetal monitoring and optimal timing of delivery. The Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT) trial compared induction of labor with expectant management in pregnancies at (near) term complicated by suspected FGR. Findings of the DIGITAT trial were that expectant monitoring prolonged pregnancy for 10 days and increased birth weight with only 130 grams. This resulted in more infants born below the 2.3rd percentile compared to induction of labor, respectively, 12.5% in induction of labor and 30.6% in expectant monitoring group. The main placental lesions associated with FGR are maternal vascular malperfusion, fetal vascular malperfusion, and villitis of unknown etiology. We investigated whether placentas of pregnancies complicated with FGR in the expectant monitoring group reveal more and more severe pathology due to pregnancy prolongation. Material and methods: The DIGITAT trial was a multicenter, randomized controlled trial with suspected FGR beyond 36 + 0 weeks. We now analyzed all available cases (n = 191) for placental pathology. The macroscopic details were collected and histological slides were recorded and classified by a single perinatal pathologist, blinded for pregnancy details and outcome. The different placental lesions were scored based on the latest international criteria for placental lesions as defined in the Amsterdam Placental Workshop Group Consensus Statement. Results: The presence of maternal vascular malperfusion and chorioamnionitis were higher in the expectant management group (p < 0.05 and p < 0.01, respectively). No differences in placental weight and maturation of the placenta between the induction of labor and the expectant management group were seen. Fetal vascular malperfusion, villitis of unknown etiology and nucleated red blood cell count did not differ between the groups. Conclusion: Expectant management of late FGR is associated with increased maternal vascular malperfusion and chorioamnionitis. This may have implications for fetal and neonatal outcome, such as programming in the developing child influencing health outcomes later in life.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30949132

RESUMO

The anti-angiogenic soluble fms-like tyrosine kinase 1 (sFLT1) is one of the candidates in the progression of preeclampsia, often associated with fetal growth restriction (FGR). Therapeutic agents against preeclampsia with/without FGR, as well as adequate transgenic sFLT1 mouse models for testing such agents, are still missing. Much is known about sFLT1-mediated endothelial dysfunction in several tissues; however, the influence of sFLT1 on placental and fetal development is currently unknown. We hypothesize that sFLT1 is involved in the progression of FGR by influencing placental differentiation and vascularization and is a prime candidate for interventional strategies. Therefore, we generated transgenic inducible human sFLT1/reverse tetracycline-controlled transactivator (hsFLT1/rtTA) mice, in which hsFLT1 is ubiquitously overexpressed during pregnancy in dams and according to the genetics in hsFLT1/rtTA homozygous and heterozygous fetuses. Induction of hsFLT1 led to elevated hsFLT1 levels in the serum of dams and on mRNA level in all placentas and hetero-/homozygous fetuses, resulting in FGR in all fetuses at term. The strongest effects in respect to FGR were observed in the hsFLT1/rtTA homozygous fetuses, which exhibited the highest hsFLT1 levels. Only fetal hsFLT1 expression led to impaired placental morphology characterized by reduced placental efficiency, enlarged maternal sinusoids, reduced fetal capillaries, and impaired labyrinthine differentiation, associated with increased apoptosis. Besides impaired placental vascularization, the expression of several transporter systems, such as glucose transporter 1 and 3 (Glut-1; Glut-3); amino acid transporters, solute carrier family 38, member one and two (Slc38a1; Slc38a2); and most severely the fatty acid translocase Cd36 and fatty acid binding protein 3 (Fabp3) was reduced upon hsFLT1 expression, associated with an accumulation of phospholipids in the maternal serum. Moreover, the Vegf pathway showed alterations, resulting in reduced Vegf, Vegfb, and Plgf protein levels and increased Bad and Caspase 9 mRNA levels. We suggest that hsFLT1 exerts an inhibitory influence on placental vascularization by reducing Vegf signaling, which leads to apoptosis in fetal vessels, impairing placental differentiation, and the nutrient exchange function of the labyrinth. These effects were more pronounced when both the dam and the fetus expressed hsFLT1 and ultimately result in FGR and resemble the preeclamptic phenotype in humans.

8.
Dis Model Mech ; 12(2)2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30683649

RESUMO

Pre-eclampsia is a multifactorial pregnancy-associated disorder characterized by angiogenic dysbalance and systemic inflammation; however, animal models that combine these two pathophysiological conditions are missing. Here, we introduce a novel double-hit pre-eclampsia mouse model that mimics the complex multifactorial conditions present during pre-eclampsia and allows for the investigation of early consequences for the fetus. Adenoviral overexpression of soluble fms-like tyrosine kinase (sFlt-1) and lipopolysaccharide (LPS) administration at mid-gestation in pregnant mice resulted in hypertension and albuminuria comparable to that of the manifestation in humans. A metabolomics analysis revealed that pre-eclamptic dams have increased plasma concentrations of phosphadytilcholines. The fetuses of both sexes were growth restricted; however, in males a brain-sparing effect was seen as compensation for this growth restriction. According to the plasma metabolomics, male fetuses showed changes in amino acid metabolism, while female fetuses showed pronounced alterations in lipid metabolism. Our results show that combined exposure to sFlt-1 and LPS mimics the clinical symptoms of pre-eclampsia and affects fetal growth in a sex-specific manner, with accompanying metabolome changes.


Assuntos
Pré-Eclâmpsia/patologia , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/patologia , Regulação da Expressão Gênica no Desenvolvimento , Lipopolissacarídeos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Metaboloma , Metabolômica , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/sangue , Placenta/metabolismo , Placenta/patologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Gravidez , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Am J Physiol Regul Integr Comp Physiol ; 315(6): R1107-R1114, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30207754

RESUMO

Intrauterine growth restriction (IUGR) is an accepted risk factor for metabolic disorders in later life, including obesity and type 2 diabetes. The level of metabolic dysregulation can vary between subjects and is dependent on the severity and the type of IUGR insult. Classical IUGR animal models involve nutritional deprivation of the mother or uterine artery ligation. The latter aims to mimic a placental insufficiency, which is the most frequent cause of IUGR. In this study, we investigated whether IUGR attributable to placental insufficiency impacts the glucose and lipid homeostasis at advanced age. Placental insufficiency was achieved by deletion of the transcription factor AP-2y ( Tfap2c), which serves as one of the major trophoblast differentiation regulators. TdelT-IUGR mice were obtained by crossing mice with a floxed Tfap2c allele and mice with Cre recombinase under the control of the Tpbpa promoter. In advanced adulthood (9-12 mo), female and male IUGR mice are respectively 20% and 12% leaner compared with controls. At this age, IUGR mice have unaffected glucose clearance and lipid parameters (cholesterol, triglycerides, and phospholipids) in the liver. However, female IUGR mice have increased plasma free fatty acids (+87%) compared with controls. This is accompanied by increased mRNA levels of fatty acid synthase and endoplasmic reticulum stress markers in white adipose tissue. Taken together, our results suggest that IUGR by placental insufficiency may lead to higher lipogenesis in female mice in advanced adulthood, at least indicated by greater Fasn expression. This effect was sex specific for the aged IUGR females.


Assuntos
Envelhecimento , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/genética , Placenta/metabolismo , Proteínas da Gravidez/metabolismo , Animais , Diferenciação Celular/genética , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Retardo do Crescimento Fetal/metabolismo , Metabolismo dos Lipídeos/fisiologia , Camundongos Transgênicos , Obesidade/metabolismo , Insuficiência Placentária/metabolismo , Gravidez , Proteínas da Gravidez/genética
10.
FASEB J ; : fj201700717RR, 2018 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-29812971

RESUMO

Postnatal overfeeding increases the risk of chronic diseases later in life, including obesity, insulin resistance, hepatic steatosis, and type 2 diabetes. Epigenetic mechanisms might underlie the long-lasting effects associated with early nutrition. Here we aimed to explore the molecular pathways involved in early development of insulin resistance and hepatic steatosis, and we examined the potential contribution of DNA methylation and histone modifications to long-term programming of metabolic disease. We used a well-characterized mouse model of neonatal overfeeding and early adiposity by litter size reduction. Neonatal overfeeding led to hepatic insulin resistance very early in life that persisted throughout adulthood despite normalizing food intake. Up-regulation of monoacylglycerol O-acyltransferase ( Mogat) 1 conceivably mediates hepatic steatosis and insulin resistance through increasing intracellular diacylglycerol content. Early and sustained deregulation of Mogat1 was associated with a combination of histone modifications that might favor Mogat1 expression. In sum, postnatal overfeeding causes extremely rapid derangements of hepatic insulin sensitivity that remain relatively stable until adulthood. Epigenetic mechanisms, particularly histone modifications, could contribute to such long-lasting effects. Our data suggest that targeting hepatic monoacylglycerol acyltransferase activity during early life might provide a novel strategy to improve hepatic insulin sensitivity and prevent late-onset insulin resistance and fatty liver disease.-Ramon-Krauel, M., Pentinat, T., Bloks, V. W., Cebrià, J., Ribo, S., Pérez-Wienese, R., Vilà, M., Palacios-Marin, I., Fernández-Pérez, A., Vallejo, M., Téllez, N., Rodríguez, M. À., Yanes, O., Lerin, C., Díaz, R., Plosch, T., Tietge, U. J. F., Jimenez-Chillaron, J. C. Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long-term hepatic steatosis and insulin resistance.

11.
Hypertension ; 71(5): 911-920, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29610268

RESUMO

Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.


Assuntos
Diabetes Gestacional/genética , Epigênese Genética/genética , Retardo do Crescimento Fetal/genética , Resistência à Insulina/genética , Prenhez , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Animais , Metilação de DNA/genética , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatologia , Diabetes Gestacional/fisiopatologia , Feminino , Hiperglicemia/genética , Hiperglicemia/fisiopatologia , Hiperinsulinismo/genética , Hiperinsulinismo/fisiopatologia , Imuno-Histoquímica , Gravidez , Ratos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estatísticas não Paramétricas
12.
Front Physiol ; 9: 1884, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30670983

RESUMO

Fetal growth restriction (FGR) is often the result of placental insufficiency and is characterized by insufficient transplacental transport of nutrients and oxygen. The main underlying entities of placental insufficiency, the pathophysiologic mechanism, can broadly be divided into impairments in blood flow and exchange capacity over the syncytiovascular membranes of the fetal placenta villi. Fetal growth restriction is not synonymous with small for gestational age and techniques to distinguish between both are needed. Placental insufficiency has significant associations with adverse pregnancy outcomes (perinatal mortality and morbidity). Even in apparently healthy survivors, altered fetal programming may lead to long-term neurodevelopmental and metabolic effects. Although the concept of fetal growth restriction is well appreciated in contemporary obstetrics, the appropriate detection of FGR remains an issue in clinical practice. Several approaches have aimed to improve detection, e.g., uniform definition of FGR, use of Doppler ultrasound profiles and use of growth trajectories by ultrasound fetal biometry. However, the role of placental morphometry (placental dimensions/shape and weight) deserves further exploration. This review article covers the clinical relevance of placental morphometry during pregnancy and at birth to help recognize fetuses who are growth restricted. The assessment has wide intra- and interindividual variability with various consequences. Previous studies have shown that a small placental surface area and low placental weight are associated with a slower growth of the fetus. Parameters such as placental surface area, placental volume and placental weight in relation to birth weight can help to identify FGR. In the future, a model including sophisticated antenatal placental morphometry may prove to be a clinically useful method for screening or diagnosing growth restricted fetuses, in order to provide optimal monitoring.

13.
Epigenetics ; 12(12): 1076-1091, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29160127

RESUMO

The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.


Assuntos
Metilação de DNA , Fator de Crescimento Insulin-Like I/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Receptores de Somatomedina/genética , Fumar Tabaco/genética , Animais , Feminino , Fígado/embriologia , Fígado/metabolismo , Pulmão/embriologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Regiões Promotoras Genéticas , Receptores de Somatomedina/metabolismo , Fatores Sexuais
14.
Sci Rep ; 7(1): 14807, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093568

RESUMO

Normal pregnancy requires adaptations of the maternal vasculature. During preeclampsia these adaptations are not well established, which may be related to maternal hypertension and proteinuria. The effects of preeclampsia on the maternal vasculature are not yet fully understood. We aimed to evaluate gene expression in aortas of pregnant rats with experimental preeclampsia using a genome wide microarray. Aortas were isolated from pregnant Wistar outbred rats with low-dose LPS-induced preeclampsia (ExpPE), healthy pregnant (Pr), non-pregnant and low-dose LPS-infused non-pregnant rats. Gene expression was measured by microarray and validated by real-time quantitative PCR. Gene Set Enrichment Analysis was performed to compare the groups. Functional analysis of the aorta was done by isotonic contraction measurements while stimulating aortic rings with potassium chloride. 526 genes were differentially expressed, and positive enrichment of "potassium channels", "striated muscle contraction", and "neuronal system" gene sets were found in ExpPE vs. Pr. The potassium chloride-induced contractile response of ExpPE aortic rings was significantly decreased compared to this response in Pr animals. Our data suggest that potassium channels, neuronal system and (striated) muscle contraction in the aorta may play a role in the pathophysiology of experimental preeclampsia. Whether these changes are also present in preeclamptic women needs further investigation.


Assuntos
Aorta/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Pré-Eclâmpsia/metabolismo , Animais , Aorta/patologia , Aorta/fisiopatologia , Feminino , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos , Ratos Wistar
15.
Placenta ; 60 Suppl 1: S41-S51, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28647398

RESUMO

Unique immunologic adaptations exist to successfully establish and maintain pregnancy and to avoid an immune attack against the semi allogenic fetus. These adaptations occur both locally at the maternofetal interface and in the peripheral circulation and affect the innate as well as the adaptive immune system. Pregnancy is characterized by a general inflammatory state with activation of monocytes and granulocytes, but also with suppressive lymphocytes (regulatory T cells), and skewing towards T helper 2 immunity. The pregnancy complication preeclampsia is associated with an exaggerated inflammatory state and predominance of T helper 1 and 17 immunity. The syncytiotrophoblast has been found to secrete extracellular vesicles as communication factors into the maternal circulation. Syncytiotrophoblast extracellular vesicles from normal pregnancy have been shown to interact with monocytes, granulocytes, T cells and natural killer cells and influence the function of these cells. In doing so, they may support the inflammatory state of normal pregnancy as well as the suppressive lymphocyte phenotype. During preeclampsia, syncytiotrophoblast extracellular vesicles are not only increased in numbers but also showed an altered molecular load. Based on data from in vitro studies, it can be suggested that syncytiotrophoblast extracellular vesicles from preeclamptic pregnancies may support the exaggerated inflammatory state during preeclampsia. In this review, we discuss the immunological functions of syncytiotrophoblast extracellular vesicles and their involvement in adapting the maternal peripheral immunological adaptations to pregnancy.


Assuntos
Vesículas Extracelulares/imunologia , Imunomodulação , Modelos Imunológicos , Pré-Eclâmpsia/imunologia , Pré-Eclâmpsia/terapia , Trofoblastos/imunologia , Imunidade Adaptativa , Animais , Distinções e Prêmios , Exossomos/imunologia , Exossomos/patologia , Exossomos/fisiologia , Vesículas Extracelulares/patologia , Vesículas Extracelulares/fisiologia , Feminino , Humanos , Imunidade Inata , Placenta/imunologia , Placenta/patologia , Placenta/fisiologia , Placenta/fisiopatologia , Pré-Eclâmpsia/patologia , Gravidez , Trofoblastos/citologia , Trofoblastos/patologia , Trofoblastos/fisiologia
16.
Gastroenterology ; 153(2): 382-385.e3, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28438611

RESUMO

In nematodes, the intestine senses and integrates early life dietary cues that lead to lifelong epigenetic adaptations to a perceived nutritional environment-it is not clear whether this process occurs in mammals. We aimed to establish a mouse model of reduced dietary cholesterol availability from maternal milk and investigate the consequences of decreased milk cholesterol availability, early in life, on the metabolism of cholesterol in adult mice. We blocked intestinal absorption of cholesterol in milk fed to newborn mice by supplementing the food of dams (for 3 weeks between birth and weaning) with ezetimibe, which is secreted into milk. Ezetimibe interacts with the intestinal cholesterol absorption transporter NPC1l1 to block cholesterol uptake into enterocytes. Characterization of these offspring at 24 weeks of age showed a 27% decrease in cholesterol absorption (P < .001) and reduced levels of Npc1l1 messenger RNA and protein, but not other cholesterol transporters, in the proximal small intestine. We observed increased histone H3K9me3 methylation at positions -423 to -607 of the proximal Npc1l1 promoter in small intestine tissues from 24-week-old offspring fed ezetimibe during lactation, compared with controls. These findings show that the early postnatal mammalian intestine functions as an environmental sensor of nutritional conditions, responding to conditions such as low cholesterol levels by epigenetic modifications of genes. Further studies are needed to determine how decreased sterol absorption for a defined period might activate epigenetic regulators; the findings of our study might have implications for human infant nutrition and understanding and preventing cardiometabolic disease.


Assuntos
Adaptação Fisiológica , Colesterol na Dieta/metabolismo , Colesterol/metabolismo , Absorção Intestinal/fisiologia , Mucosa Intestinal/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Disponibilidade Biológica , Transporte Biológico , Enterócitos/metabolismo , Epigênese Genética , Ezetimiba/farmacologia , Feminino , Histonas/metabolismo , Absorção Intestinal/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestinos/citologia , Lactação/fisiologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Camundongos , Leite/química , Modelos Animais , RNA Mensageiro/metabolismo
17.
Mol Nutr Food Res ; 61(1)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27129739

RESUMO

SCOPE: The long-lasting consequences of nutritional programming during the early phase of life have become increasingly evident. The effects of maternal nutrition on the developing intestine are still underexplored. METHODS AND RESULTS: In this study, we observed (1) altered microbiota composition of the colonic luminal content, and (2) differential gene expression in the intestinal wall in 2-week-old mouse pups born from dams exposed to a Western-style (WS) diet during the perinatal period. A sexually dimorphic effect was found for the differentially expressed genes in the offspring of WS diet-exposed dams but no differences between male and female pups were found for the microbiota composition. Integrative analysis of the microbiota and gene expression data revealed that the maternal WS diet independently affected gene expression and microbiota composition. However, the abundance of bacterial families not affected by the WS diet (Bacteroidaceae, Porphyromonadaceae, and Lachnospiraceae) correlated with the expression of genes playing a key role in intestinal development and functioning (e.g. Pitx2 and Ace2). CONCLUSION: Our data reveal that maternal consumption of a WS diet during the perinatal period alters both gene expression and microbiota composition in the intestinal tract of 2-week-old offspring.


Assuntos
Dieta Ocidental/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica , Intestino Delgado/fisiologia , Exposição Materna , Animais , Animais Recém-Nascidos , Colo/fisiologia , Feminino , Microbioma Gastrointestinal/genética , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S , Fatores Sexuais
18.
J Steroid Biochem Mol Biol ; 169: 198-201, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27215141

RESUMO

Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serum cholesterol concentrations are regulated by enteral absorption, biliary secretion, and hepatic synthesis. Statins inhibit the rate-limiting enzyme of cholesterol synthesis, HMG-CoA-reductase, and reduce serum cholesterol concentrations as well as cardiovascular morbidity and mortality. Some studies indicate that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Data from genetic association studies and from the IMPROVE-IT trial show that reducing intestinal cholesterol absorption via NCP1L1 further reduces cardiovascular risk. However, some patients do not attain LDL-cholesterol targets on combination therapy. For these patients PCSK9-antibody treatment and lipid-apheresis are options to be considered. This article reviews the current literature on this issue and suggests 'individualized lipid-lowering therapy' as an approach to optimize and personalize lipid-lowering treatment of patients with hypercholesterolemia to further reduce residual cardiovascular risk.


Assuntos
Cardiologia/métodos , Doenças Cardiovasculares/prevenção & controle , Hipolipemiantes/farmacologia , Lipídeos/química , Animais , Remoção de Componentes Sanguíneos , Colesterol/química , LDL-Colesterol/química , Estudos de Associação Genética , Humanos , Hidroximetilglutaril-CoA Redutases/metabolismo , Hipercolesterolemia/prevenção & controle , Pró-Proteína Convertase 9/metabolismo , Risco , Fatores de Risco
19.
J Cell Biochem ; 118(6): 1316-1329, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27859593

RESUMO

Since it is known that placental overexpression of the human anti-angiogenic molecule sFlt-1, the main candidate in the progression of preeclampsia, lead to intrauterine growth restriction (IUGR) in mice by lentiviral transduction of mouse blastocysts, we hypothesize that sFlt-1 influence placental morphology and physiology resulting in fetal IUGR. We therefore examined the effect of sFlt-1 on placental morphology and physiology at embryonic day 18.5 with histologic and morphometric analyses, transcript analyses, immunoblotting, and methylation studies. Interestingly, placental overexpression of sFlt-1 leads to IUGR in the fetus and results in lower placental weights. Moreover, we observed altered trophoblast differentiation with reduced expression of IGF2, resulting in a smaller placenta, a smaller labyrinth, and the loss of glycogen cells in the junctional zone. Changes in IGF2 are accompanied by small changes in its DNA methylation, whereas overall DNA methylation is unaffected. In addition, the expression of placental nutrient transporters, such as the glucose diffusion channel Cx26, is decreased. In contrast, the expression of the fatty acid transporter CD36 and the cholesterol transporter ABCA1 is significantly increased. In conclusion, placental sFlt-1 overexpression resulted in a reduction in the differentiation of the spongiotrophoblast into glycogen cells. These findings of a reduced exchange area of the labyrinth and glycogen stores, as well as decreased expression of glucose transporter, could contribute to the intrauterine growth restriction phenotype. All of these factors change the intrauterine availability of nutrients. Thus, we speculate that the alterations triggered by increased anti-angiogenesis strongly affect fetal outcome and programming. J. Cell. Biochem. 118: 1316-1329, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Retardo do Crescimento Fetal/genética , Placenta/patologia , Trofoblastos/citologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciação Celular , Conexinas/genética , Conexinas/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Epigênese Genética , Feminino , Retardo do Crescimento Fetal/patologia , Glicogênio/metabolismo , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Placenta/metabolismo , Gravidez , Trofoblastos/metabolismo
20.
Reprod Fertil Dev ; 29(10): 1921-1931, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27918728

RESUMO

In the rabbit reproductive model, maternal experimentally induced insulin-dependent diabetes mellitus (expIDD) leads to accumulation of lipid droplets in blastocysts. Cholesterol metabolism is a likely candidate to explain such metabolic changes. Therefore, in the present study we analysed maternal and embryonic cholesterol concentrations and expression of related genes in vivo (diabetic model) and in vitro (embryo culture in hyperglycaemic medium). In pregnant expIDD rabbits, the serum composition of lipoprotein subfractions was changed, with a decrease in high-density lipoprotein cholesterol and an increase in very low-density lipoprotein cholesterol; in uterine fluid, total cholesterol concentrations were elevated. Expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), very low-density lipoprotein receptor (VLDLR), sterol regulatory element binding transcription factor 2 (SREBF2), insulin-induced gene-1 (INSIG1) and cholesterol 7α-hydroxylase (CYP7A1) mRNA was decreased in the liver and low-density lipoprotein receptor (LDLR) mRNA expression was decreased in the adipose tissue of diabetic rabbits. In embryos from diabetic rabbits, the mean (±s.e.m.) ratio of cholesterol concentrations in trophoblasts to embryoblasts was changed from 1.27±2.34 (control) to 0.88±3.85 (expIDD). Rabbit blastocysts expressed HMGCR, LDLR, VLDLR, SREBF2 and INSIG1 but not CYP7A1, without any impairment of expression as a result of maternal diabetes. In vitro hyperglycaemia decreased embryonic HMGCR and SREBF2 transcription in rabbit blastocysts. The findings of the present study show that a diabetic pregnancy leads to distinct changes in maternal cholesterol metabolism with a minor effect on embryo cholesterol metabolism.


Assuntos
Blastocisto/metabolismo , Colesterol/metabolismo , Diabetes Mellitus Experimental/metabolismo , Metabolismo dos Lipídeos/fisiologia , Animais , Feminino , Fígado/metabolismo , Gravidez , Coelhos , Receptores de LDL/metabolismo , Triglicerídeos/metabolismo
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