RESUMO
OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.
Assuntos
Glucose , Comportamento Sedentário , Exercício Físico , Feminino , Humanos , Recém-Nascido , Estilo de Vida , Metabolismo dos Lipídeos/genética , Obesidade/complicações , Placenta/metabolismo , Gravidez , Resultado da Gravidez , Gestantes , RNA MensageiroRESUMO
During development, the human fetus accrues the highest proportion of fat of all mammals. Precursors of fat lobules can be found at week 14 of pregnancy. Thereafter, they expand, filling with triacylglycerols during pregnancy. The resultant mature lipid-filled adipocytes emerge from a developmental programme of embryonic stem cells, which is regulated differently than adult adipogenesis. Fetal triacylglycerol synthesis uses glycerol and fatty acids derived predominantly from glycolysis and lipogenesis in liver and adipocytes. The fatty acid composition of fetal adipose tissue at the end of pregnancy shows a preponderance of palmitic acid, and differs from the mother. Maternal diabetes mellitus does not influence this fatty acid profile. Glucose oxidation is the main source of energy for the fetus, but mitochondrial fatty acid oxidation also contributes. Indirect evidence suggests the presence of lipoprotein lipase in fetal adipose tissue. Its activity may be increased under hyperinsulinemic conditions as in maternal diabetes mellitus and obesity, thereby contributing to increased triacylglycerol deposition found in the newborns of such pregnancies. Fetal lipolysis is low. Changes in the expression of genes controlling metabolism in fetal adipose tissue appear to contribute actively to the increased neonatal fat mass found in diabetes and obesity. Many of these processes are under endocrine regulation, principally by insulin, and show sex-differences. Novel fatty acid derived signals such as oxylipins are present in cord blood with as yet undiscovered function. Despite many decades of research on fetal lipid deposition and metabolism, many key questions await answers.
Assuntos
Diabetes Mellitus , Metabolismo dos Lipídeos , Adipogenia , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus/metabolismo , Feminino , Feto/metabolismo , Humanos , Recém-Nascido , Obesidade/metabolismo , GravidezRESUMO
AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.
Assuntos
Glicemia/metabolismo , Cesárea/estatística & dados numéricos , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/metabolismo , Macrossomia Fetal/epidemiologia , Idade Gestacional , Insulina/metabolismo , Obesidade Materna/epidemiologia , Adulto , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Secreção de Insulina , Fenótipo , GravidezRESUMO
OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2 = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.
Assuntos
Peso ao Nascer , Exercício Físico , Macrossomia Fetal/epidemiologia , Recém-Nascido Pequeno para a Idade Gestacional , Tecido Adiposo , Adulto , Estudos de Coortes , Diabetes Gestacional/epidemiologia , Metabolismo Energético , Feminino , Humanos , Recém-Nascido , Modelos Lineares , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Fatores de Proteção , Fatores de Risco , Adulto JovemRESUMO
The first trimester of pregnancy is characterized by continuous proliferation, invasion and differentiation of cytotrophoblasts. These processes are precisely controlled both, in space and time by molecules such as endothelin-1 (ET-1). ET-1 is expressed in human first trimester trophoblast and is known to stimulate cytotrophoblast proliferation through endothelin A and B receptor subtypes (ET(A) and ET(B)), and cytotrophoblast invasion through ET(B). However, temporal changes of the ET system during the first trimester of pregnancy have not been previously studied. This study tested the hypothesis that ET-1 release, ET(A) and ET(B) expression are increased towards the end of the first trimester of pregnancy (weeks 10-12 vs. weeks 6-9), resulting in increased cytotrophoblast proliferation and invasion. Tissue samples were obtained from 17 surgical pregnancy interruptions (week 6-9: n=9; week 10-12: n=8). After cytotrophoblast isolation, the invasive and proliferative phenotypes were immune-separated by an alpha(6)-integrin antibody. Both proliferative and invasive cytotrophoblasts were cultured separately on plastic or Matrigel for 24 h. ET-1 release into the culture medium of both cytotrophoblast subtypes was measured by radioimmunoassay. ET(A) and ET(B) mRNA expression was measured by RT-PCR, and the ET-1 effect on cytotrophoblast proliferation and invasion was determined using proliferation and invasion assays, respectively. ET-1 release increased from early to late first trimester of pregnancy in both proliferative (1.8-4.5 fold) and invasive cytotrophoblasts (9.3-28 fold), especially when cultured on Matrigel. This was paralleled by less ET(B) mRNA on invasive cytotrophoblasts independent of the time period in first trimester, whereas ET(A) expression was similar on proliferative an invasive cytotrophoblasts. Proliferation and invasion of cytotrophoblasts under control conditions decreased from early to late first trimester. ET-1 stimulated both processes at both periods with the most pronounced effect (7-fold) on invasion in late first trimester. The ET-1/ET-receptor system changes between weeks 6-9 and 10-12 in pregnancy. Our data suggest an autocrine and endocrine ET-1 effect, which is stronger in late than in early first trimester of pregnancy paralleled by different stimulatory effects on trophoblast invasion and proliferation. In general, this suggests time as an additional effector of the critical processes governing placental development in the first trimester of human pregnancy.
Assuntos
Endotelina-1/metabolismo , Placenta/citologia , Placenta/metabolismo , Primeiro Trimestre da Gravidez/metabolismo , Receptor de Endotelina A/metabolismo , Trofoblastos/metabolismo , Proliferação de Células/fisiologia , Células Cultivadas , Feminino , Humanos , Gravidez , Fatores de TempoRESUMO
BACKGROUND: Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero, but little is known about the role of placental metabolism and its contribution to fetal development. OBJECTIVES: We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. SUBJECTS/METHODS: Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. RESULTS: Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04-1.24 mg g-1, P<0.05) vs lean (0.84, CI 0.72-1.02 mg g-1) women. Among target genes examined, six showed positive correlation (P<0.05) with maternal pre-pregnancy BMI, namely ATGL (PNPLA2), FATP1 (SLC27A1), FATP3 (SLC27A3), PLIN2, PPARG and CGI-58 (ABHD5). CGI-58 protein abundance was twofold higher (P<0.001) in placentas of obese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index (R=0.63, P<0.001 and R=0.64, P<0.001, respectively). CGI-58 and PLIN2 were primarily located in the syncytiotrophoblast and, were upregulated (1.38- and 500-fold, respectively) upon oleic acid and insulin treatment of cultured trophoblast cells. CONCLUSION: Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother.
Assuntos
Metabolismo dos Lipídeos/fisiologia , Lipogênese/fisiologia , Obesidade/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Nascimento a Termo , Magreza/metabolismo , Adulto , Cesárea , Feminino , Desenvolvimento Fetal , Humanos , Recém-Nascido , Resistência à Insulina , Troca Materno-Fetal , Obesidade/complicações , Obesidade/fisiopatologia , Gravidez , Complicações na Gravidez/fisiopatologiaRESUMO
The human placenta comprises a special type of tissue macrophages, the Hofbauer cells (HBC), which exhibit M2 macrophage phenotype. Several subtypes of M2-polarized macrophages (M2a, M2b and M2c) exist in almost all tissues. Macrophage polarization depends on the way of macrophage activation and leads to the expression of specific cell surface markers and the acquisition of specific functions, including tissue remodeling and the promotion of angiogenesis. The placenta is a highly vascularized and rapidly growing organ, suggesting a role of HBC in feto-placental angiogenesis. We here aimed to characterize the specific polarization and phenotype of HBC and investigated the role of HBC in feto-placental angiogenesis. Therefore, HBC were isolated from third trimester placentas and their phenotype was determined by the presence of cell surface markers (FACS analysis) and secretion of cytokines (ELISA). HBC conditioned medium (CM) was analyzed for pro-angiogenic factors, and the effect of HBC CM on angiogenesis, proliferation and chemoattraction of isolated primary feto-placental endothelial cells (fpEC) was determined in vitro Our results revealed that isolated HBC possess an M2 polarization, with M2a, M2b and M2c characteristics. HBC secreted the pro-angiogenic molecules VEGF and FGF2. Furthermore, HBC CM stimulated the in vitro angiogenesis of fpEC. However, compared with control medium, chemoattraction of fpEC toward HBC CM was reduced. Proliferation of fpEC was not affected by HBC CM. These findings demonstrate a paracrine regulation of feto-placental angiogenesis by HBC in vitro Based on our collective results, we propose that the changes in HBC number or phenotype may affect feto-placental angiogenesis.
Assuntos
Biomarcadores/metabolismo , Células Endoteliais/citologia , Feto/irrigação sanguínea , Macrófagos/citologia , Placenta/irrigação sanguínea , Adulto , Células Cultivadas , Citocinas/metabolismo , Feminino , Feto/citologia , Feto/fisiologia , Humanos , Masculino , Neovascularização Fisiológica , Fenótipo , Placenta/citologia , Placenta/fisiologia , GravidezRESUMO
BACKGROUND: Excessive fat accumulation characterizes the over-nourished fetus in maternal diabetes and obesity with fetal insulin regarded as a primary driver. This study tested whether fetal insulin is related to subcutaneous adipose tissue (SAT) thickness at different body sites in neonates, and whether sites respond differentially to insulin. In addition, sex differences were assessed. METHODS: Cord blood insulin was measured for 414 neonates. After birth, SAT thickness was measured at 15 body sites using a validated device, a lipometer, that measures back-scattered light intensities corresponding to SAT. Associations between fetal insulin and SAT were assessed in linear regression models, adjusted for gestational age and birth weight, for males and females separately. RESULTS: No sex differences in insulin levels or total SAT thickness were found. In males, SAT thickness at most body sites was significantly correlated with insulin, with strongest associations between insulin and SAT on neck (beta 0.23, 95% CI 0.05; 0.41; P=0.01) and upper abdomen (beta 0.18, 95% CI 0.01; 0.36; P=0.04). In females, insulin was only associated with hip SAT thickness (beta 0.22, 95% CI 0.06; 0.39; P=0.01). Total SAT thickness was correlated with insulin in males (beta 0.03, 95% CI 0.01; 0.04; P=0.003), but not in females (beta 0.01, 95% CI -0.01; 0.02; P=0.38). CONCLUSIONS: Fat deposition in female neonates seems less affected by insulin as compared to males. This may reflect lower insulin sensitivity in females, or may be accounted for by other metabolic/endocrine factors overriding the association.
Assuntos
Sangue Fetal/metabolismo , Hiperglicemia/fisiopatologia , Insulina/sangue , Mães , Complicações na Gravidez/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Gordura Subcutânea/metabolismo , Áustria/epidemiologia , Composição Corporal , Feminino , Humanos , Hiperglicemia/sangue , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores SexuaisRESUMO
Pregnancy is a complex period of human growth, development, and imprinting. Nutrition and metabolism play a crucial role for the health and well-being of both mother and fetus, as well as for the long-term health of the offspring. Nevertheless, several biological and physiological mechanisms related to nutritive requirements together with their transfer and utilization across the placenta are still poorly understood. In February 2009, the Child Health Foundation invited leading experts of this field to a workshop to critically review and discuss current knowledge, with the aim to highlight priorities for future research. This paper summarizes our main conclusions with regards to maternal preconceptional body mass index, gestational weight gain, placental and fetal requirements in relation to adverse pregnancy and long-term outcomes of the fetus (nutritional programming). We conclude that there is an urgent need to develop further human investigations aimed at better understanding of the basis of biochemical mechanisms and pathophysiological events related to maternal-fetal nutrition and offspring health. An improved knowledge would help to optimize nutritional recommendations for pregnancy.
Assuntos
Saúde Global , Transtornos da Nutrição do Lactente/prevenção & controle , Fenômenos Fisiológicos da Nutrição Materna , Modelos Biológicos , Política Nutricional , Cooperação do Paciente , Complicações na Gravidez/prevenção & controle , Adulto , Desenvolvimento Infantil , Feminino , Desenvolvimento Fetal , Humanos , Transtornos da Nutrição do Lactente/epidemiologia , Recém-Nascido , Estado Nutricional , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Risco , Aumento de PesoRESUMO
Fatty acids are critical for normal fetal growth and development. The placenta mediates the transfer of fatty acids from the maternal to the fetal circulation. Yet, the mechanisms of fatty acid transport are not fully understood. The development of a computational model alongside experiments will test our understanding of the transfer mechanisms. Modelling experimental data suggest the presence of a metabolic pool within placental tissue that could represent the rate-limiting factor for fatty acid transfer. In addition the model suggests a slower flux capacity of the fetal-side of the placenta compared with the maternal-side. The model provides key insights into placental fatty acid transfer which will form the basis for future experimentation.
Assuntos
Placenta , Transporte Biológico , Ácidos Graxos , Feminino , Feto , Humanos , Troca Materno-Fetal , GravidezRESUMO
Trophoblast invasion into uterine tissues represents a hallmark of first trimester placental development. As expression of serum amyloid A4 (SAA4) occurs in tumorigenic and invasive tissues we here investigated whether SAA4 is present in trophoblast-like human AC1-M59/Jeg-3 cells and trophoblast preparations of human first trimester and term placenta. SAA4 mRNA was expressed in non-stimulated and cytokine-treated AC1-M59/Jeg-3 cells. In purified trophoblast cells SAA4 mRNA expression was upregulated at weeks 10 and 12 of pregnancy. Western-blot and immunohistochemical staining of first trimester placental tissue revealed pronounced SAA4 expression in invasive trophoblast cells indicating a potential role of SAA4 during invasion.
Assuntos
Proteína Amiloide A Sérica/metabolismo , Trofoblastos/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Terceiro Trimestre da GravidezRESUMO
Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2013 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) diabetes in pregnancy; 2) lipids, fatty acids and the placenta; 3) oxygen in placental development and pathologies; 4) stem cells and pathologies.
Assuntos
Diabetes Gestacional/metabolismo , Dislipidemias/fisiopatologia , Oxigênio/fisiologia , Placentação , Animais , Feminino , Desenvolvimento Fetal , Humanos , Gravidez , Transdução de Sinais , Células-Tronco/fisiologiaRESUMO
Offspring of obese and diabetic mothers are at increased risk of being born with excess adiposity as a consequence of their intrauterine environment. Excessive fetal fat accretion reflects additional placental nutrient transfer, suggesting an effect of the maternal environment on placental function. High plasma levels of particular nutrients in obese and diabetic mothers are likely to be the important drivers of nutrient transfer to the fetus, resulting in excess fat accretion. However, not all offspring of obese and diabetic mothers are born large for gestational age and the explanation may involve the regulation of placental nutrient transfer required for fetal growth. The placenta integrates maternal and fetal signals across gestation in order to determine nutrient transfer rate. Understanding the nature of these signals and placental responses to them is key to understanding the pathology of both fetal growth restriction and macrosomia. The overall effects of the maternal environment on the placenta are the product of its exposures throughout gestation, the 'placental exposome'. Understanding these environmental influences is important as exposures early in gestation, for instance causing changes in the function of genes involved in nutrient transfer, may determine how the placenta will respond to exposures later in gestation, such as to raised maternal plasma glucose or lipid concentrations. Longitudinal studies are required which allow investigation of the influences on the placenta across gestation. These studies need to make full use of developing technologies characterising placental function, fetal growth and body composition. Understanding these processes will assist in the development of preventive strategies and treatments to optimise prenatal growth in those pregnancies at risk of either excess or insufficient nutrient supply and could also reduce the risk of chronic disease in later life.
Assuntos
Adiposidade , Composição Corporal/fisiologia , Feto/metabolismo , Placentação , Peso ao Nascer , Epigênese Genética , Feminino , Desenvolvimento Fetal , Humanos , Troca Materno-Fetal , Obesidade/metabolismo , Gravidez , Resultado da Gravidez , Fatores de RiscoRESUMO
Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2012 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology: 1) epigenetics and imprinting in the placenta; 2) growth factors and villous trophoblast differentiation; 3) role of the placenta in regulating fetal exposure to xenobiotics during pregnancy; 4) infection and the placenta.
Assuntos
Epigênese Genética/fisiologia , Impressão Genômica/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Placenta/fisiologia , Complicações Infecciosas na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Trofoblastos/fisiologia , Xenobióticos/efeitos adversos , Diferenciação Celular/fisiologia , Feminino , Humanos , Placenta/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologiaRESUMO
CONTEXT: Gestational diabetes mellitus (GDM)-associated hormonal and metabolic derangements in mother and fetus affect placental development and function. Indeed, in GDM, placentas are characterized by hypervascularization and vascular dysfunction. The membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key player in angiogenesis and vascular expansion. OBJECTIVE: Here, we hypothesized elevated placental MT1-MMP levels in GDM induced by components of the diabetic environment. Therefore, we measured placental MT1-MMP in normal vs. GDM pregnancies, identified potential functional consequences, and investigated the contribution of hyperglycemia and the insulin/IGF axis. DESIGN: Immunohistochemistry identified placental cell types expressing MT1-MMP. MT1-MMP was compared between normal and GDM placentas by immunoblotting. Quantitative PCR of MT1-MMP in primary feto-placental endothelial cells (fpEC) and trophoblasts isolated from both normal and GDM placentas identified the cells contributing to the GDM-associated changes. A putative MT1-MMP role in angiogenesis was determined using blocking antibodies for in vitro angiogenesis assays. Potential GDM-associated factors and signaling pathways inducing MT1-MMP up-regulation in fpEC were identified using kinase inhibitors. RESULTS: Total and active MT1-MMP was increased in GDM placentas (+51 and 54%, respectively, P<0.05) as a result of up-regulated expression in fpEC (2.1-fold, P=0.02). MT1-MMP blocking antibodies reduced in vitro angiogenesis up to 25% (P=0.03). Pathophysiological levels of insulin and IGF-II, but not IGF-I and glucose, stimulated MT1-MMP expression in fpEC by phosphatidylinositol 3-kinase signals relayed through the insulin, but not IGF-I, receptor. CONCLUSIONS: GDM up-regulates MT1-MMP in the feto-placental endothelium, and insulin and IGF-II contribute. This may account for GDM-associated changes in the feto-placental vasculature.
Assuntos
Diabetes Gestacional/metabolismo , Feto/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Insulina/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Placenta/metabolismo , Adulto , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Neovascularização Fisiológica/fisiologia , Placenta/irrigação sanguínea , Placenta/citologia , Gravidez , Terceiro Trimestre da Gravidez/metabolismo , Cultura Primária de Células , Trofoblastos/citologia , Trofoblastos/metabolismo , Regulação para Cima/fisiologiaRESUMO
Pregestational obesity is a significant risk factor for adverse pregnancy outcomes. Maternal obesity is associated with a specific proinflammatory, endocrine and metabolic phenotype that may lead to higher supply of nutrients to the feto-placental unit and to excessive fetal fat accumulation. In particular, obesity may influence placental fatty acid (FA) transport in several ways, leading to increased diffusion driving force across the placenta, and to altered placental development, size and exchange surface area. Animal models show that maternal obesity is associated with increased expression of specific FA carriers and inflammatory signaling molecules in placental cotyledonary tissue, resulting in enhanced lipid transfer across the placenta, dislipidemia, fat accumulation and possibly altered development in fetuses. Cell culture experiments confirmed that inflammatory molecules, adipokines and FA, all significantly altered in obesity, are important regulators of placental lipid exchange. Expression studies in placentas of obese-diabetic women found a significant increase in FA binding protein-4 expression and in cellular triglyceride content, resulting in increased triglyceride cord blood concentrations. The expression and activity of carriers involved in placental lipid transport are influenced by the endocrine, inflammatory and metabolic milieu of obesity, and further studies are needed to elucidate the strong association between maternal obesity and fetal overgrowth.
Assuntos
Ácidos Graxos/metabolismo , Obesidade/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Transporte Biológico , Feminino , Humanos , Metabolismo dos Lipídeos , Troca Materno-Fetal , GravidezRESUMO
Objective. Assess the impact of Gestational Diabetes Mellitus (GDM) and obesity on neonatal and maternal pregnancy outcomes. Methods. Cross-sectional data (3343 pregnancies) from seven European centres were included in a multilevel analysis of the association between GDM/obesity and caesarean section, macrosomia and neonatal morbidities. Results. Comparison of databases identified reporting differences between countries due to the inclusion of true population based samples or pregnancies from specialised tertiary centres, resulting in higher prevalences of GDM for some countries. The analysis showed that obesity and GDM were independent risk factors of perinatal complications. Only BMI had a dose-dependent effect on the risk of macrosomia and caesarean section. Both obesity (BMI > 30 kg/m(2)) and GDM were independent risk factors of neonatal morbidities. Conclusions. Obesity and GDM were independent risk factors of perinatal complications. The effect of the worldwide obesity and diabetes epidemic is extending to the next generation.
RESUMO
PURPOSE: Excessive fetal fat as the hallmark of GDM pregnancy complications is one consequence of fetal hyperinsulinism. Noninvasive methods for fetal surveillance and measurement of fetal fat are needed. The purpose of this study was to test the hypothesis that measurements of the fetal anterior abdominal wall thickness (AAWT) in women with GDM will allow early detection of fetal hyperinsulinism. MATERIALS AND METHODS: Amniocentesis was performed between 28 and 32 weeks of gestation (wks) in 220 women with GDM (diagnosed by 75 g oGTT at 24 to 28 wks). Amniotic fluid insulin levels (AFIL) were determined by a commercially available radioimmunoassay. Transabdominal ultrasound provided fetal biometric measurements following standard procedures and the AAWT including fetal skin and subcutaneous tissue at the time of amniocentesis. Maternal parameters (weight, BMI, oGTT blood glucose levels and mean daily blood glucose levels) were correlated with fetal biometric data and with AFIL. RESULTS: There was no difference in AAWT in women with GDM and no correlation with mean AFIL. AFIL also did not correlate with any other fetal measurement or with mean oGTT blood glucose levels. AFIL only showed a correlation with maternal weight (p = 0.02) and maternal BMI (p = 0.01). The correlation was present for values both before pregnancy and at the time of amniocentesis. CONCLUSION: In the early third trimester, AAWT measurements do not correlate with fetal insulin levels.
Assuntos
Parede Abdominal/diagnóstico por imagem , Tecido Adiposo/diagnóstico por imagem , Líquido Amniótico/metabolismo , Diabetes Gestacional/diagnóstico por imagem , Desenvolvimento Fetal/fisiologia , Hiperinsulinismo/diagnóstico por imagem , Insulina/metabolismo , Dobras Cutâneas , Ultrassonografia Pré-Natal , Parede Abdominal/embriologia , Tecido Adiposo/embriologia , Adulto , Amniocentese , Índice de Massa Corporal , Peso Corporal/fisiologia , Estudos de Coortes , Feminino , Idade Gestacional , Teste de Tolerância a Glucose , Humanos , Hiperinsulinismo/embriologia , Recém-Nascido , Gravidez , Terceiro Trimestre da Gravidez , Radioimunoensaio , Estudos Retrospectivos , Estatística como Assunto , Tela Subcutânea/embriologia , Tela Subcutânea/fisiologiaRESUMO
By its location between maternal and fetal bloodstreams the human placenta not only handles the materno-fetal transport of nutrients and gases, but may also be exposed to intrauterine conditions adversely affecting placental and fetal development. Such adverse conditions exist in pregnancies complicated by gestational diabetes mellitus (GDM), and have been associated with alterations in placental anatomy and physiology. These alterations are mainly based on changes on the micro-anatomical and/or even molecular level including aberrant villous vascularization, a disbalance of vasoactive molecules, and enhanced oxidative stress. The consequence thereof may be impaired fetal oxygenation and changes in transplacental nutrient supply. Although transplacental glucose flux is flow limited and independent of glucose transporter availability, transport of essential and nonessential amino acids and expression of genes involved in lipid transport and metabolism are significantly affected by GDM.
Assuntos
Diabetes Gestacional/fisiopatologia , Obesidade/fisiopatologia , Placenta/patologia , Estado Pré-Diabético/fisiopatologia , Peso ao Nascer , Glicemia/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Humanos , Obesidade/metabolismo , Tamanho do Órgão , Estresse Oxidativo , Placenta/metabolismo , Placenta/fisiopatologia , Estado Pré-Diabético/metabolismo , Gravidez , Gravidez de Alto RiscoRESUMO
CONTEXT: Endothelin-1 (ET-1) stimulates proliferation and invasion of first-trimester human trophoblast cells. OBJECTIVE: To test the hypothesis that ET-1 effects are mediated by different receptor subtypes [ET receptor (ETR)-A and ETR-B]. DESIGN: The location of ETR in trophoblast cell columns (wk 6-12) was investigated by immunohistochemistry and autoradiography. Trophoblasts were isolated from first-trimester human placentas and proliferative and invasive subpopulations separated using an integrin α6 antibody. Cells were incubated for 24 h with 10 µm ET-1 and different ETR antagonists: PD142893 (unselective), BQ-610 (ETR-A), and RES-701-1 (ETR-B). After ETR down-regulation by antisense oligonucleotides, proliferation (thymidine incorporation, protein synthesis) and invasion (Matrigel invasion) were measured. ETR expression in isolated cells was analyzed by Western blotting and semiquantitative RT-PCR. RESULTS: Both ETR are expressed in both subpopulations in the cell column with predominance of ETR-A in the proximal part and proliferative subpopulation, whereas ETR-B is present at similar levels in both subpopulations. These results were confirmed at the mRNA level. ET-1 increased proliferation (maximum 267% of control) and invasion (maximum 288% of control) of first-trimester trophoblasts. The mitogenic ET-1 effect was inhibited (P < 0.05) by 40-80% with each receptor antagonist and by 44 and 40%, respectively, by ETR-A and ETR-B antisense oligonucleotides. The invasion-promoting effect was almost completely blocked in the presence of the ETR-B antagonists. CONCLUSION: The effect of ET-1 on cell proliferation in first-trimester trophoblasts is mediated by both ETR, whereas its effect on invasion is mediated predominantly by ETR-B. These effects are in line with the receptor subtype location.