RESUMEN
SCOPE: Glucose intolerance during pregnancy is associated with short- and long-term maternal and offspring health consequences. In young male mice, knockout of the major pro-inflammatory mediator interleukin-1-receptor-1 (IL1R1) protects against high-fat diet (HFD)-induced glucose intolerance and metabolic dysfunction. This phenotype has not been examined during pregnancy. The hypothesis that IL1R1 depletion will protect females against HFD-induced glucose intolerance and metabolic dysfunction before, during, and post pregnancy is tested. METHODS AND RESULTS: C57BL/6J control and IL1R1 knockout (IL1R1-/- ) mice are randomized to either a control diet (10% kcal from fat) or HFD (45% kcal from fat), and three distinct cohorts are established: nulliparous, pregnant, and postpartum females. Contrary to the authors' hypothesis, it is found that IL1R1-/- does not protect against glucose intolerance in nulliparous or pregnant females, and while control HFD animals see a resolution of glucose tolerance postpartum, IL-1R1-/- mice remain impaired. These effects are accompanied by adipocyte hypertrophy, hyperleptinemia, and increased adipose tissue inflammatory gene expression. Maternal genotype differentially affects fetal growth in male and female fetuses, demonstrating sexual dimorphism in this genotype prior to birth. CONCLUSIONS: These findings suggest that IL1R1 signaling is important for normal metabolic functioning in females, during and outside of pregnancy.
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Tejido Adiposo/fisiopatología , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/etiología , Receptores Tipo I de Interleucina-1/metabolismo , Animales , Femenino , Desarrollo Fetal , Expresión Génica , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Paniculitis/etiología , Paniculitis/genética , Placenta/fisiología , Periodo Posparto , Embarazo , Receptores Tipo I de Interleucina-1/deficiencia , Receptores Tipo I de Interleucina-1/genéticaRESUMEN
Background: The global incidence of obesity continues to rise, increasing the prevalence of metabolic diseases such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus. Low-grade chronic inflammation, associated with the obese state, also contributes to the development of these metabolic comorbidities. Interleukin-1-receptor-1 (IL-1R1), a pro-inflammatory mediator, bridges the metabolic and inflammatory systems. In young male mice, deficiency of IL-1R1 (IL-1R1-/-) paired with a high-fat diet (HFD) offered beneficial metabolic effects, however in female mice, the same pairing led to metabolic dysfunction. Therefore, we examined the contribution of maternal HFD in combination with IL1R1-/- to metabolic health in adult offspring. Methods: Female C57BL/6 and IL-1R1-/- mice were randomly assigned to a control diet (10% kcal from fat) or HFD (45% kcal from fat) 10 days prior to mating and throughout gestation and lactation. Male and female offspring were housed in same-sex pairs post-weaning and maintained on control diets until 16 weeks old. At 15 weeks, an oral glucose tolerance test (OGTT) was performed to assess glucose tolerance. Histological analysis was carried out to assess adipocyte size and gene expression of adipogenic and inflammatory markers were examined. Results: IL-1R1-/- contributed to increased body weight in male and female adult offspring, irrespective of maternal diet. IL-1R1-/- and maternal HFD increased adipocyte size in the gonadal fat depot of female, but not male offspring. In female offspring, there was reduced expression of genes involved in adipogenesis and lipid metabolism in response to IL1R1-/- and maternal HFD. While there was an increase in inflammatory gene expression in response to maternal HFD, this appeared to be reversed in IL1R1-/- female offspring. In male offspring, there was no significant impact on adipogenic or lipid metabolism pathways. There was an increase in inflammatory gene expression in IL1R1-/- male offspring from HFD-fed mothers. Conclusion: This study suggests that IL-1R1 plays a complex and important role in the metabolic health of offspring, impacting adipogenesis, lipogenesis, and inflammation in a sex-specific manner.
RESUMEN
BACKGROUND: Sugar-sweetened beverage consumption is associated with metabolic dysfunction. Artificially sweetened beverages (ASBs) are often promoted as an alternative. However, evidence for the safety of ASB consumption during pregnancy is lacking. OBJECTIVES: The effects of sugar-sweetened beverage and ASB consumption during pregnancy in mice were examined, and we hypothesized that both sugar-sweetened beverages and ASBs would impair maternal metabolic function. METHODS: Pregnant female C57BL/6J mice received control drinking water (CD), high-fructose corn syrup (Fr; 20% kcal intake; 335 mM), or the artificial sweetener acesulfame potassium (AS; 12.5 mM) in their drinking water, from gestational day (GD) 0.5 (n = 8/group). Body weights and food and water intakes were assessed every second day, an oral-glucose-tolerance test (OGTT) was performed at GD 16.5, and mice were culled at GD 18.5. RT-PCR was carried out on adipose tissue, liver, and gut. Adipose tissue morphology was assessed using histological methods. In a separate cohort of animals, pregnancy length was assessed. Repeated-measures ANOVA was performed for the OGTT and weight gain data. All other data were analyzed by 1-way ANOVA. RESULTS: Fr and AS significantly impaired glucose tolerance, as demonstrated by OGTT (21% and 24% increase in AUC, respectively; P = 0.0006). Fr and AS reduced expression of insulin receptor (39.5% and 33% reduction, respectively; P = 0.02) and peroxisome proliferator-activated receptor γ (45.2% and 47%, respectively; P = 0.039), whereas Fr alone reduced expression of protein kinase B (36.9% reduction; P = 0.048) and resulted in an increase in adipocyte size and leptin concentrations (40% increase; P = 0.03). AS, but not Fr, reduced male fetal weight (16.5% reduction; P = 0.04) and female fetal fasting blood glucose concentration at cull (20% reduction; P = 0.02) compared with CD. AS significantly reduced the length of pregnancy compared with the CD and Fr groups (1.25 d shorter; P = 0.02). CONCLUSIONS: Fr and AS consumption were associated with maternal metabolic dysfunction in mice. AS was also associated with reduced fetal growth and fetal hypoglycemia. Therefore, ASBs may not be a beneficial alternative to sugar-sweetened beverages during pregnancy.
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Tejido Adiposo/efectos de los fármacos , Intolerancia a la Glucosa/inducido químicamente , Efectos Tardíos de la Exposición Prenatal , Edulcorantes , Tiazinas/efectos adversos , Adipocitos/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Dieta , Femenino , Feto/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Tiazinas/administración & dosificaciónRESUMEN
PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) is a common pregnancy complication that has short- and long-term health implications for both the mother and child. While lifestyle modifications, insulin therapy, and oral agents such as metformin are effective, they can be difficult to adhere to, and there remain concerns over long-term effects of oral agents on the infant. Further, GDM has no proven preventive strategies, which could be more effective than treatment postdiagnosis. Nutritional supplements are an appealing, potentially safer, and better tolerated alternative to pharmaceuticals to treat and/or prevent GDM. Here, we review the existing evidence for nutritional supplementation for treatment and prevention of GDM. RECENT FINDINGS: There is limited evidence that myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics might be beneficial for the prevention or treatment of GDM. There are very few studies for each nutrient, and the existing studies tend to have few participants. Where multiple studies of a nutrient exist, often those studies were conducted within the same country, limiting the generalizability of the findings, or alternatively there was no consensus across findings. There is limited evidence that nutritional supplementation of myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics could improve glycemic control or prevent GDM. Our understanding is constrained by the small number of studies, small sample sizes in most studies, and by lack of consistency across findings. Further large, high-quality, randomized controlled trials are required to determine the efficacy of nutritional supplements to treat or prevent GDM.
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Diabetes Mellitus Tipo 2/terapia , Diabetes Gestacional/terapia , Suplementos Dietéticos , Glucemia/análisis , Niño , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/prevención & control , Diabetes Gestacional/sangre , Diabetes Gestacional/dietoterapia , Diabetes Gestacional/prevención & control , Femenino , Humanos , Micronutrientes/administración & dosificación , Embarazo , Factores de RiesgoRESUMEN
BACKGROUND/AIMS: Gestational diabetes mellitus (GDM) is closely associated with early perinatal complications and long-term health problems, such as cardiovascular disease, in offspring. AMP-activated protein kinase (AMPK) is cardioprotective, particularly in the treatment of ischemia/reperfusion (I/R). However, whether GDM programs offspring susceptibility to cardiac I/R and the involvement of AMPK remain unclear. METHODS: Streptozotocin was administered to rats during mid pregnancy; the postpartum maternal metabolome was assessed by chromatography-mass spectrometry (GC-MS). Male offspring were subjected to body composition scanning followed by ex vivo global I/R. Cardiac signaling was determined by Western blotting. RESULTS: The body weights (BWs) of the GDM male offspring were significantly heavier than those of the control group from the age of 8 weeks; the heart weights (HWs) and HW/BW were also increased in the GDM group compared to the control group. The ex vivo post-I/R cardiac contractile function recovery was significantly compromised in the GDM male offspring. The phosphorylation of AMPK and ACC was elevated by ex vivo I/R in both groups, but to a significantly lesser extent in the GDM group. CONCLUSION: GDM male offspring rats have higher risks of overgrowth and intolerance to cardiac I/R, which may be due to a compromised AMPK signaling pathway.
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Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Gestacional/enzimología , Contracción Miocárdica , Daño por Reperfusión Miocárdica/enzimología , Transducción de Señal , Animales , Diabetes Gestacional/inducido químicamente , Diabetes Gestacional/patología , Femenino , Masculino , Daño por Reperfusión Miocárdica/patología , Tamaño de los Órganos , Embarazo , RatasRESUMEN
Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic ß-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist-including insulin and lifestyle interventions-there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.
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Diabetes Gestacional/fisiopatología , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , Animales , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/etiología , Diabetes Gestacional/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Leptina/metabolismo , Estrés Oxidativo , Embarazo , Factores de RiesgoRESUMEN
Fetal growth restriction (FGR) is associated with an increased risk of hypertension, insulin resistance, obesity and cardiovascular disease in adulthood. Currently there are no effective treatments to reverse the course of FGR. This study used the eNOS knockout mouse (eNOS-/-), a model of FGR, to determine the ability of sildenafil, a potential new treatment for FGR, to improve cardiovascular and metabolic outcomes in adult offspring following a complicated pregnancy. Pregnant eNOS-/- and C57BL/6J control dams were randomised to sildenafil treatment (0.2 mg/ml in drinking water) or placebo at day 12.5 of gestation until birth. After weaning, male offspring were randomised to either a high fat (HFD; 45% kcal from fat) or normal chow diet (ND), and raised to either postnatal day 90 or 150. Growth and body composition, glucose tolerance, insulin resistance, systolic blood pressure and vascular function were analysed at both time-points. eNOS-/- offspring were significantly smaller than their C57BL/6J controls at weaning and P90 (p < 0.01); at P150 they were a similar weight. Total adipose tissue deposition at P90 was significantly increased only in eNOS-/- mice fed a HFD (p < 0.001). At P150 both C57BL/6J and eNOS-/- offspring fed a HFD demonstrated significant adipose tissue deposition (p < 0.01), regardless of maternal treatment. Both diet and maternal sildenafil treatment had a significant effect on glucose tolerance. Glucose tolerance was significantly impaired in eNOS-/- mice fed a HFD (p < 0.01); this was significant in offspring from both sildenafil and vehicle treated mothers at P90 and P150. Glucose tolerance was also impaired in C57BL/6J mice fed a HFD at both P90 and P150 (p < 0.01), but only in those also exposed to sildenafil. In these C57BL/6J mice, sildenafil was associated with impaired insulin sensitivity at P90 (p = 0.020) but increased insulin resistance at P150 (p = 0.019). Exposure to sildenafil was associated with a significant increase in systolic blood pressure in eNOS-/- mice compared with their C57BL/6J diet controls at P150 (p < 0.05). Exposure to sildenafil had differing effects on vascular function in mesenteric arteries; it increased vasodilation in response to ACh in C57BL/6J mice, but was associated with a more constrictive phenotype in eNOS-/- mice. eNOS-/- mice demonstrate a number of impaired outcomes consistent with programmed cardiometabolic disease, particularly when faced with the 'second hit' of a HFD. Exposure to sildenafil treatment during pregnancy did not increase fetal growth or significantly improve adult metabolic or cardiac outcomes. Maternal sildenafil treatment was, however, associated with small impairments in glucose handling and an increase in blood pressure. This study highlights the importance of understanding the long-term effects of treatment during pregnancy in offspring from both complicated and healthy control pregnancies.
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Retardo del Crecimiento Fetal/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo III/genética , Citrato de Sildenafil/uso terapéutico , Adiposidad/efectos de los fármacos , Animales , Glucemia/análisis , Presión Sanguínea , Dieta Alta en Grasa , Femenino , Insulina/sangre , Masculino , Intercambio Materno-Fetal , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , EmbarazoRESUMEN
Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.
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Hormona del Crecimiento/metabolismo , Hormonas Placentarias/metabolismo , Complicaciones del Embarazo/metabolismo , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional/metabolismo , Síndrome de Down/metabolismo , Femenino , Retardo del Crecimiento Fetal/metabolismo , Macrosomía Fetal/metabolismo , Enfermedad Trofoblástica Gestacional/metabolismo , Humanos , Embarazo , Embarazo en Diabéticas/metabolismo , Embarazo Ectópico/metabolismo , Isoformas de Proteínas , Síndrome de la Trisomía 18/metabolismoRESUMEN
STUDY QUESTION: How do nano-vesicles extruded from normal first trimester human placentae affect maternal vascular function? SUMMARY ANSWER: Placental nano-vesicles affect the ability of systemic mesenteric arteries to undergo endothelium- and nitric oxide- (NO-) dependent vasodilation in vivo in pregnant mice. WHAT IS KNOWN ALREADY: Dramatic cardiovascular adaptations occur during human pregnancy, including a substantial decrease in total peripheral resistance in the first trimester. The human placenta constantly extrudes extracellular vesicles that can enter the maternal circulation and these vesicles may play an important role in feto-maternal communication. STUDY DESIGN, SIZE, DURATION: Human placental nano-vesicles were administered into CD1 mice via a tail vein and their localization and vascular effects at 30 min and 24 h post-injection were investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Nano-vesicles from normal first trimester human placentae were collected and administered into pregnant (D12.5) or non-pregnant female mice. After either 30 min or 24 h of exposure, all major organs were dissected for imaging (n = 7 at each time point) while uterine and mesenteric arteries were dissected for wire myography (n = 6 at each time point). Additional in vitro studies using HMEC-1 endothelial cells were also conducted to investigate the kinetics of interaction between placental nano-vesicles and endothelial cells. MAIN RESULTS AND THE ROLE OF CHANCE: Nano-vesicles from first trimester human placentae localized to the lungs, liver and kidneys 24 h after injection into pregnant mice (n = 7). Exposure of pregnant mice to placental nano-vesicles for 30 min in vivo increased the vasodilatory response of mesenteric arteries to acetylcholine, while exposure for 24 h had the opposite effect (P < 0.05, n = 6). These responses were prevented by L-NAME, an NO synthase inhibitor. Placental nano-vesicles did not affect the function of uterine arteries or mesenteric arteries from non-pregnant mice. Placental nano-vesicles rapidly interacted with endothelial cells via a combination of phagocytosis, endocytosis and cell surface binding in vitro. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: As it is not ethical to administer labelled placental nano-vesicles to pregnant women, pregnant CD1 mice were used as a model of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to report the localization of placental nano-vesicles and their vascular effects in vivo. This work provides new insight into how the dramatic maternal cardiovascular adaptations to pregnancy may occur and indicates that placental extracellular vesicles may be important mediators of feto-maternal communication in a healthy pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Faculty of Medical and Health Science (FMHS) School of Medicine PBRF research fund to L.W.C. M.T. is a recipient of a University of Auckland Health Research Doctoral Scholarship and the Freemasons Postgraduate Scholarship. No authors have any competing interests to disclose.
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Vesículas Extracelulares/trasplante , Arterias Mesentéricas/fisiología , Placenta/fisiología , Arteria Uterina/fisiología , Vasodilatación/fisiología , Animales , Femenino , Humanos , Riñón/fisiología , Hígado/fisiología , Pulmón/fisiología , Ratones , Miografía , Embarazo , Resistencia Vascular/fisiologíaRESUMEN
Treatment options for gestational diabetes (GDM) are limited. In order to better understand mechanisms and improve treatments, appropriate animal models of GDM are crucial. Heterozygous db mice (db/+) present with glucose intolerance, insulin resistance, and increased weight gain during, but not prior to, pregnancy. This makes them an ideal model for GDM. However, several recent studies have reported an absence of GDM phenotype in their colony. We investigated several hypotheses for why the phenotype may be absent, with the aim of re-establishing it and preventing further resources being wasted on an ineffective model. Experiments were carried out across two laboratories in two countries (New Zealand and China), and were designed to assess type of control strain, diet, presence of the misty allele, and parity as potential contributors to the lost phenotype. While hyperleptinemia and pre-pregnancy weight gain were present in all db/+mice across the four studies, we found no consistent evidence of glucose intolerance or insulin resistance during pregnancy. In conclusion, we were unable to acquire the GDM phenotype in any of our experiments, and we recommend researchers do not use the db/+ mouse as a model of GDM unless they are certain the phenotype remains in their colony.
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Diabetes Gestacional/genética , Fenotipo , Receptores de Leptina/genética , Alelos , Animales , Diabetes Gestacional/patología , Dieta , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Paridad , EmbarazoRESUMEN
Gestational diabetes mellitus (GDM) is a growing concern, affecting an increasing number of pregnant women worldwide. By predisposing both the affected mothers and children to future disease, GDM contributes to an intergenerational cycle of obesity and diabetes. In order to stop this cycle, safe and effective treatments for GDM are required. This study sought to determine the treatment effects of dietary supplementation with myo-inositol (MI) and vitamins B2, B6, B12, and D in a mouse model of GDM (pregnant db/+ dams). In addition, the individual effects of vitamin B2 were examined. Suboptimal B2 increased body weight and fat deposition, decreased GLUT4 adipose tissue expression, and increased expression of inflammatory markers. MI supplementation reduced weight and fat deposition, and reduced expression of inflammatory markers in adipose tissue of mice on suboptimal B2. MI also significantly reduced the hyperleptinemia observed in db/+ mice, when combined with supplemented B2. MI was generally associated with adipose tissue markers of improved insulin sensitivity and glucose uptake, while the combination of vitamins B2, B6, B12, and D was associated with a reduction in adipose inflammatory marker expression. These results suggest that supplementation with MI and vitamin B2 could be beneficial for the treatment/prevention of GDM.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Gestacional/tratamiento farmacológico , Suplementos Dietéticos , Inositol/administración & dosificación , Riboflavina/administración & dosificación , Vitamina D/administración & dosificación , Vitaminas/administración & dosificación , Tejido Adiposo/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/metabolismo , Ratones , EmbarazoRESUMEN
Exogenous growth hormone has different actions depending on the method of administration. However, the effects of different modes of administration of the placental variant of growth hormone on growth, body composition and glucose metabolism have not been investigated. In this study, we examined the effect of pulsatile vs. continuous administration of recombinant variant of growth hormone in a normal mouse model. Female C57BL/6J mice were randomized to receive vehicle or variant of growth hormone (2 or 5 mg/kg per day) by daily subcutaneous injection (pulsatile) or osmotic pump for 6 days. Pulsatile treatment with 2 and 5 mg/kg per day significantly increased body weight. There was also an increase in liver, kidney and spleen weight via pulsatile treatment, whereas continuous treatment did not affect body weight or organ size. Pulsatile treatment with 5 mg/kg per day significantly increased fasting plasma insulin concentration, whereas with continuous treatment, fasting insulin concentration was not significantly different from the vehicle-treated control. However, a dose-dependent increase in fasting insulin concentration and decrease in insulin sensitivity, as assessed by HOMA, was observed with both modes of treatment. At 5 mg/kg per day, hepatic growth hormone receptor expression was increased compared to vehicle-treated animals, by both modes of administration. Pulsatile variant of growth hormone did not alter the plasma insulin-like growth factor-1 concentration, whereas a slight decrease was observed with continuous variant of growth hormone treatment. Neither pulsatile nor continuous treatment affected hepatic insulin-like growth factor-1 mRNA expression. Our findings suggest that pulsatile variant of growth hormone treatment was more effective in stimulating growth but caused marked hyperinsulinemia in mice.
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Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hormona de Crecimiento Humana/administración & dosificación , Animales , Glucemia/metabolismo , Línea Celular , Esquema de Medicación , Femenino , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Bazo/efectos de los fármacosRESUMEN
Intrauterine growth restriction (IUGR) causes short- and long-term morbidity. Reduced placental perfusion is an important pathogenic component of IUGR; substances that enhance vasodilation in the uterine circulation, such as sildenafil citrate (sildenafil), may improve placental blood flow and fetal growth. This study aimed to examine the effects of sildenafil in the growth-restricted ovine fetus. Ewes carrying singleton pregnancies underwent insertion of vascular catheters, and then, they were randomized to receive uterine artery embolization (IUGR) or to a control group. Ewes in the IUGR group received a daily infusion of sildenafil (IUGR+SC; n=10) or vehicle (IUGR+V; n=8) for 21 days. The control group received no treatment (n=9). Umbilical artery blood flow was measured using Doppler ultrasound and the resistive index (RI) calculated. Fetal weight, biometry, and placental weight were obtained at postmortem after treatment completion. Umbilical artery RI in IUGR+V fell less than in controls; the RI of IUGR+SC was intermediate to that of the other 2 groups (mean±SEM for control versus IUGR+V versus IUGR+SC: ∆RI, 0.09±0.03 versus -0.01±0.02 versus 0.03±0.02; F(2, 22)=4.21; P=0.03). Compared with controls, lamb and placental weights were reduced in IUGR+V but not in IUGR+SC (control versus IUGR+V versus IUGR+SC: fetal weight, 4381±247 versus 3447±235 versus 3687±129 g; F(2, 24)=5.49; P=0.01 and placental weight: 559.7±35.0 versus 376.2±32.5 versus 475.2±42.5 g; F(2, 24)=4.64; P=0.01). Sildenafil may be a useful adjunct in the management of IUGR. An increase in placental weight and fall in fetal-placental resistance suggests that changes to growth are at least partly mediated by changes to placental growth rather than alterations in placental efficiency.
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Desarrollo Fetal/efectos de los fármacos , Retardo del Crecimiento Fetal/tratamiento farmacológico , Placentación/efectos de los fármacos , Preñez , Citrato de Sildenafil/administración & dosificación , Resistencia Vascular/efectos de los fármacos , Animales , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/prevención & control , Circulación Placentaria/efectos de los fármacos , Embarazo , Distribución Aleatoria , Valores de Referencia , Flujo Sanguíneo Regional , Ovinos , Arteria UterinaRESUMEN
BACKGROUND: Preeclampsia is known to be associated with reduced circulating levels of estrogen. The effects of estrogen in preeclampsia are normally mediated by the classical estrogen receptors. Intriguingly, a novel estrogen receptor, G protein-coupled receptor 30 (GPR30), has been recently found to play an important role in several estrogenic effects. However, the mechanisms by which GPR30 may mediate the development of preeclampsia remain unknown. METHOD: We observed that the expression of GPR30 in placental trophoblast cells is lower in preeclamptic placentas compared with normotensive controls. We then investigated the role of GPR30 in trophoblast cell invasion by utilizing placental explants and the immortalized human trophoblast cell line (HTR8/SVneo). RESULTS: The selective GPR30 agonist G1 and a general estrogen receptors agonist 17-ß-estradiol (E2) both improved trophoblast cells invasion by upregulating MMP9 expression and the PI3K-Akt signaling pathway. This effect was abolished by a selective GPR30 inhibitor G15, implying that GPR30 may be involved in regulating trophoblast invasion, and that down-regulation of this receptor may result in the development of preeclampsia. CONCLUSION: The present study suggests that GPR30 is a critical regulator of trophoblast cell invasion, and as such may be a potential therapeutic interventional target for preeclampsia and other pregnancy complications resulting from impaired trophoblast invasion.
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Placenta , Preeclampsia , Receptores de Estrógenos/fisiología , Receptores Acoplados a Proteínas G/fisiología , Trofoblastos , Línea Celular , Femenino , Humanos , Placenta/metabolismo , Placenta/fisiología , Preeclampsia/metabolismo , Preeclampsia/fisiopatología , Embarazo , Trofoblastos/metabolismo , Trofoblastos/fisiologíaRESUMEN
The human placental GH variant (GH-V) is secreted continuously from the syncytiotrophoblast layer of the placenta during pregnancy and is thought to play a key role in the maternal adaptation to pregnancy. Maternal GH-V concentrations are closely related to fetal growth in humans. GH-V has also been proposed as a potential candidate to mediate insulin resistance observed later in pregnancy. To determine the effect of maternal GH-V administration on maternal and fetal growth and metabolic outcomes during pregnancy, we examined the dose-response relationship for GH-V administration in a mouse model of normal pregnancy. Pregnant C57BL/6J mice were randomized to receive vehicle or GH-V (0.25, 1, 2, or 5 mg/kg · d) by osmotic pump from gestational days 12.5 to 18.5. Fetal linear growth was slightly reduced in the 5 mg/kg dose compared with vehicle and the 0.25 mg/kg groups, respectively, whereas placental weight was not affected. GH-V treatment did not affect maternal body weights or food intake. However, treatment with 5 mg/kg · d significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5 as assessed by homeostasis model assessment. At 5 mg/kg · d, there was also an increase in maternal hepatic GH receptor/binding protein (Ghr/Ghbp) and IGF binding protein 3 (Igfbp3) mRNA levels, but GH-V did not alter maternal plasma IGF-1 concentrations or hepatic Igf-1 mRNA expression. Our findings suggest that at higher doses, GH-V treatment can cause hyperinsulinemia and is a likely mediator of the insulin resistance associated with late pregnancy.
Asunto(s)
Hormona de Crecimiento Humana/farmacología , Resistencia a la Insulina , Insulina/metabolismo , Hormonas Placentarias/farmacología , Preñez/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Proteínas Portadoras/efectos de los fármacos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Femenino , Desarrollo Fetal/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Embarazo , Preñez/metabolismo , ARN Mensajero/efectos de los fármacos , Proteínas Recombinantes/farmacología , Trofoblastos/metabolismoRESUMEN
Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT(-/-)) and endothelial nitric oxide synthase (Nos3(-/-)) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT(-/-) mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3(-/-), COMT(-/-) and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3(-/-) and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT(-/-) mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT(-/-) mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT(-/-) mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action.
Asunto(s)
Catecol O-Metiltransferasa/genética , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Metaboloma/efectos de los fármacos , Preeclampsia/genética , Preeclampsia/metabolismo , Citrato de Sildenafil/farmacología , Animales , Catecol O-Metiltransferasa/metabolismo , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal/tratamiento farmacológico , Metabolómica/métodos , Ratones , Ratones Noqueados , Preeclampsia/tratamiento farmacológico , EmbarazoRESUMEN
INTRODUCTION: Preeclampsia is a disorder of pregnancy, typically characterized by hypertension and proteinuria observed after the 20th week of gestation. Preeclampsia has dire consequences for both maternal and neonatal health: it is associated with 50,000 - 100,000 annual deaths globally, as well as serious fetal and neonatal morbidity and mortality, including increased risk of fetal growth restriction and still birth. Despite the severe health, social, and economic costs of preeclampsia, currently the only curative therapy is delivery of the baby and placenta, which itself carries the associated risks of premature birth. The lack of treatments for this condition is attributable to a number of causes, including but not limited to: a partial understanding of the complex pathophysiological mechanisms underlying this complex disease; an inability to sensitively predict women who will go on to develop the disease; and a paucity of robust animal models with which to test new treatments. AREAS COVERED: Recently, progress has been made in identifying potential new therapeutic targets. This review will discuss in detail the evidence supporting further investigation of these targets, which include angiogenic factors, agents that increase vasodilation, anti-inflammatory drugs, substances that reduce oxidative stress, and statins. EXPERT OPINION: New therapeutic targets have the potential to make a significant positive impact on maternal and neonatal health. It is exciting that a number of potential therapies are currently being investigated; however, it is also vital that basic research continues to identify potential mechanisms and targets, and that any potential therapy is thoroughly tested before progression to clinical trial.
Asunto(s)
Diseño de Fármacos , Terapia Molecular Dirigida , Preeclampsia/tratamiento farmacológico , Animales , Femenino , Humanos , Recién Nacido , Estrés Oxidativo/efectos de los fármacos , Preeclampsia/fisiopatología , EmbarazoRESUMEN
Preeclampsia (PE) and fetal growth restriction (FGR) contribute significantly to fetal and maternal morbidity and mortality. Although the causes of PE and FGR are not fully understood, both conditions are known to be associated with impaired uterine artery blood flow. Resveratrol, a polyphenol found in a number of plants, has been shown to induce relaxation of uterine arteries in vitro as well as improve many pathological conditions associated with PE and FGR. We hypothesized that treatment of endothelial nitric oxide synthase knockout mice (eNOSâ»/â») and catechol-O-methyltransferase knockout mice (COMTâ»/â») with resveratrol during pregnancy would improve uterine artery blood flow and therefore ameliorate the PE-like phenotype and FGR in these murine models. Pregnant C57BL/6J, eNOSâ»/â» and COMTâ»/â» mice received either resveratrol supplemented diet (4 g/kg diet) or control diet between gestational day (GD) 0.5 and GD 18.5. Resveratrol supplementation significantly increased uterine artery blood flow velocity and fetal weight in COMTâ»/â» but not in eNOSâ»/â» mice. There were no effects of resveratrol on litter size and placental weight among the groups. In conclusion, resveratrol increased uterine artery blood flow velocity and fetal weight in COMTâ»/â» mice, suggesting potential as a therapeutic strategy for PE and FGR.
Asunto(s)
Retardo del Crecimiento Fetal/tratamiento farmacológico , Preeclampsia/tratamiento farmacológico , Flujo Sanguíneo Regional/fisiología , Estilbenos/farmacología , Útero/irrigación sanguínea , Análisis de Varianza , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Catecol O-Metiltransferasa/genética , Femenino , Peso Fetal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Acústica , Óxido Nítrico Sintasa de Tipo III/genética , Embarazo , Proteinuria , Flujo Sanguíneo Regional/efectos de los fármacos , Resveratrol , Estilbenos/uso terapéuticoRESUMEN
Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to "placental insufficiency": inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS(-/-)) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS(-/-) fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS(-/-) dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS(-/-) fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal (14)C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent (14)C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS(-/-) fetuses, indicating diminished placental nutrient transport. eNOS(-/-) mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS(-/-) mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates "uteroplacental hypoxia," providing a new framework for understanding the etiology of FGR in human pregnancy.
Asunto(s)
Retardo del Crecimiento Fetal/fisiopatología , Modelos Animales , Óxido Nítrico Sintasa de Tipo III/deficiencia , Fenotipo , Placenta/fisiopatología , Arteria Uterina/fisiopatología , Sistema de Transporte de Aminoácidos A/metabolismo , Animales , Transporte Biológico/fisiología , Presión Sanguínea/fisiología , Femenino , Retardo del Crecimiento Fetal/metabolismo , Peso Fetal/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/genética , Placenta/metabolismo , Embarazo , Proteinuria/metabolismo , Proteinuria/fisiopatología , Superóxidos/metabolismoRESUMEN
A low-resistance/high-flow uteroplacental circulation is integral to a healthy pregnancy. Impaired flow in the uterine circulation is associated with intrauterine growth restriction (IUGR) and preeclampsia (PE). Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme which has been associated with oxidative stress-induced vascular dysfunction. Using the endothelial nitric oxide synthase (eNOS(-/ -)) knockout mouse model, which features vascular dysfunction and IUGR, we tested the hypothesis that administration of a PARP inhibitor may ameliorate the vascular dysfunction associated with the eNOS(-/-) model. eNOS(-/-) animals were characterized by impaired uterine artery function when compared to controls. Administration of the PARP inhibitor PJ34 prevented this dysfunction. Gestational day (GD) 17.5 eNOS(-/-) mice did not exhibit altered systolic blood pressure when compared to control mice. However, treatment of eNOS(-/-) mice with PJ34 significantly reduced systolic blood pressure when compared to vehicle-treated eNOS(-/-). Administration of a PARP inhibitor protects uterine artery function in the face of eNOS(-/-) deficiency.