Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Physiol ; 602(6): 1211-1225, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38381050

RESUMO

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy ± daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.


Assuntos
Placenta , Artéria Uterina , Humanos , Ratos , Animais , Gravidez , Feminino , Placenta/metabolismo , Artéria Uterina/fisiologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Roedores , Óxido Nítrico/metabolismo , Ratos Wistar , Hipóxia , Proteína Quinase C/metabolismo , Mitocôndrias/metabolismo
2.
Diabetologia ; 65(12): 2132-2145, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36112170

RESUMO

AIMS/HYPOTHESIS: Metformin is increasingly used to treat gestational diabetes (GDM) and pregnancies complicated by pregestational type 2 diabetes or polycystic ovary syndrome but data regarding long-term offspring outcome are lacking in both human studies and animal models. Using a mouse model, this study investigated the effects of maternal metformin intervention during obese glucose-intolerant pregnancy on adiposity, hepatic steatosis and markers of metabolic health of male and female offspring up to the age of 12 months. METHODS: C57BL/6J female mice were weaned onto either a control diet (Con) or, to induce pre-conception obesity, an obesogenic diet (Ob). The respective diets were maintained throughout pregnancy and lactation. These obese dams were then randomised to the untreated group or to receive 300 mg/kg oral metformin hydrochloride treatment (Ob-Met) daily during pregnancy. In male and female offspring, body weights and body composition were measured from 1 month until 12 months of age, when serum and tissues were collected for investigation of adipocyte cellularity (histology), adipose tissue inflammation (histology and quantitative RT-PCR), and hepatic steatosis and fibrosis (histochemistry and modified Folch assay). RESULTS: At 12 months of age, male Ob and Ob-Met offspring showed increased adiposity, adipocyte hypertrophy, elevated expression of proinflammatory genes, hyperleptinaemia and hepatic lipid accumulation compared with Con offspring. Male Ob-Met offspring failed to show hyperplasia between 8 weeks and 12 months, indicative of restricted adipose tissue expansion, resulting in increased immune cell infiltration and ectopic lipid deposition. Female Ob offspring were relatively protected from these phenotypes but Ob-Met female offspring showed increased adiposity, adipose tissue inflammation, hepatic lipid accumulation, hyperleptinaemia and hyperinsulinaemia compared with Con female offspring. CONCLUSIONS/INTERPRETATION: Maternal metformin treatment of obese dams increased offspring metabolic risk factors in a sex- and age-dependent manner. These observations highlight the importance of following up offspring of both sexes beyond early adulthood after interventions during pregnancy. Our findings illustrate the complexity of balancing short-term benefits to mother and child vs any potential long-term metabolic effects on the offspring when prescribing therapeutic agents that cross the placenta.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Fígado Gorduroso , Metformina , Efeitos Tardios da Exposição Pré-Natal , Humanos , Gravidez , Animais , Camundongos , Criança , Masculino , Feminino , Adulto , Lactente , Metformina/farmacologia , Metformina/uso terapêutico , Glucose , Diabetes Mellitus Tipo 2/tratamento farmacológico , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Composição Corporal , Fígado Gorduroso/patologia , Inflamação , Lipídeos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Dieta Hiperlipídica/efeitos adversos
3.
J Physiol ; 600(4): 903-919, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34505282

RESUMO

Maternal obesity is a global problem that increases the risk of short- and long-term adverse outcomes for mother and child, many of which are linked to gestational diabetes mellitus. Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6/J) model of diet-induced (high sugar/high fat) maternal obesity to explore the impact of metformin on maternal and feto-placental health. Metformin (300 mg kg-1  day-1 ) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669 ± 568 nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (P < 0.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7 ± 125.4 nmol g-1 in the placenta and 2063 ± 2327 nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk vs. benefits that are weighed in obstetric medical treatments. KEY POINTS: Maternal obesity and gestational diabetes mellitus have detrimental short- and long-term effects for mother and child. Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown. In a mouse model of diet-induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth. Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity-induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue. Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long-term consequences postnatally.


Assuntos
Intolerância à Glucose , Metformina , Obesidade Materna , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Retardo do Crescimento Fetal , Intolerância à Glucose/metabolismo , Humanos , Transmissão Vertical de Doenças Infecciosas , Metformina/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Placenta/metabolismo , Gravidez
4.
Int J Obes (Lond) ; 46(2): 269-278, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34663892

RESUMO

OBJECTIVE: This study investigated the effect of maternal obesity on aged-male offspring liver phenotype and hepatic expression of a programmed miRNA. METHODS: A mouse model (C57BL/6 J) of maternal diet-induced obesity was used to investigate fasting-serum metabolites, hepatic lipid content, steatosis, and relative mRNA levels (RT-PCR) and protein expression (Western blotting) of key components involved in hepatic and mitochondrial metabolism in 12-month-old offspring. We also measured hepatic lipid peroxidation, mitochondrial content, fibrosis stage, and apoptosis in the offspring. To investigate potential mechanisms leading to the observed phenotype, we also measured the expression of miR-582 (a miRNA previously implicated in liver cirrhosis) in 8-week-old and 12-month-old offspring. RESULTS: Body weight and composition was similar between 8-week-old offspring, however, 12-month-old offspring from obese mothers had increased body weight and fat mass (19.5 ± 0.8 g versus 10.4 ± 0.9 g, p < 0.001), as well as elevated serum levels of LDL and leptin and hepatic lipid content (21.4 ± 2.1 g versus 12.9 ± 1.8 g, p < 0.01). This was accompanied by steatosis, increased Bax/Bcl-2 ratio, and overexpression of p-SAPK/JNK, Tgfß1, Map3k14, and Col1a1 in the liver. Decreased levels of Bcl-2, p-AMPKα, total AMPKα and mitochondrial complexes were also observed. Maternal obesity was associated with increased hepatic miR-582-3p (p < 0.001) and miR-582-5p (p < 0.05). Age was also associated with an increase in both miR-582-3p and miR-582-5p, however, this was more pronounced in the offspring of obese dams, such that differences were greater in 12-month-old animals (-3p: 7.34 ± 1.35 versus 1.39 ± 0.50, p < 0.0001 and -5p: 4.66 ± 1.16 versus 1.63 ± 0.65, p < 0.05). CONCLUSION: Our findings demonstrate that maternal diet-induced obesity has detrimental effects on offspring body composition as well as hepatic phenotype that may be indicative of accelerated-ageing phenotype. These whole-body and cellular phenotypes were associated with age-dependent changes in expression of miRNA-582 that might contribute mechanistically to the development of metabolic disorders in the older progeny.


Assuntos
Comportamento Alimentar/psicologia , Fígado/metabolismo , Doenças Metabólicas/dietoterapia , Fatores Etários , Animais , Modelos Animais de Doenças , Feminino , Expressão Gênica/fisiologia , Fígado/fisiopatologia , Exposição Materna/efeitos adversos , Exposição Materna/estatística & dados numéricos , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL/metabolismo , Obesidade/complicações , Obesidade/dietoterapia , RNA Mensageiro
5.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360870

RESUMO

BACKGROUND: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. METHODS: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. RESULTS: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. CONCLUSIONS: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.


Assuntos
Animais Recém-Nascidos/metabolismo , Diabetes Gestacional , Metformina/farmacologia , Obesidade Materna , Efeitos Tardios da Exposição Pré-Natal , Adiposidade , Animais , Diabetes Gestacional/tratamento farmacológico , Diabetes Gestacional/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade Materna/tratamento farmacológico , Obesidade Materna/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Fatores Sexuais
6.
FASEB J ; 35(5): e21446, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33788974

RESUMO

Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2 ) pregnancy ± MitoQ (500 µM day-1 ) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, ß-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1 -adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy.


Assuntos
Antioxidantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Hipóxia Fetal/complicações , Mitocôndrias/metabolismo , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar
7.
Diabetologia ; 64(4): 890-902, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33501603

RESUMO

AIMS/HYPOTHESIS: Levels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model. METHODS: miR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic-hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue. RESULTS: The proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance. CONCLUSIONS/INTERPRETATION: Concurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Células 3T3-L1 , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Proteínas de Homeodomínio/genética , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Obesidade Materna/genética , Obesidade Materna/patologia , Fenótipo , Gravidez , Transdução de Sinais
8.
FASEB J ; 34(7): 9664-9677, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32502311

RESUMO

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off-target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the chicken embryo, a model system in which the effects on the developing heart and circulation of therapy can be investigated, independent of effects on the mother and/or the placenta. Fertilized chicken eggs were incubated and divided randomly into control (C) or dexamethasone (Dex) treatment at day 14 out of the 21-day incubation period. Combining functional experiments at the isolated organ, cellular and molecular levels, embryos were then studied close to term. Chicken embryos exposed to dexamethasone were growth restricted and showed systolic and diastolic dysfunction, with an increase in cardiomyocyte volume but decreased cardiomyocyte nuclear density in the left ventricle. Underlying mechanisms included a premature switch from tissue accretion to differentiation, increased oxidative stress, and activated signaling of cellular senescence. These findings, therefore, demonstrate that dexamethasone treatment can have direct detrimental off-target effects on the cardiovascular system in the developing embryo, which are independent of effects on the mother and/or placenta.


Assuntos
Senescência Celular , Dexametasona/toxicidade , Fibrose/patologia , Glucocorticoides/toxicidade , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Embrião de Galinha , Galinhas , Fibrose/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos
9.
Int J Obes (Lond) ; 44(5): 1087-1096, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203108

RESUMO

BACKGROUND: In utero exposure to obesity is consistently associated with increased risk of metabolic disease, obesity and cardiovascular dysfunction in later life despite the divergence of birth weight outcomes. The placenta plays a critical role in offspring development and long-term health, as it mediates the crosstalk between the maternal and fetal environments. However, its phenotypic and molecular modifications in the context of maternal obesity associated with fetal growth restriction (FGR) remain poorly understood. METHODS: Using a mouse model of maternal diet-induced obesity, we investigated changes in the placental transcriptome through RNA sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) at embryonic day (E) 19. The most differentially expressed genes (FDR < 0.05) were validated by Quantitative real-time PCR (qPCR) in male and female placentae at E19. The expression of these targets and related genes was also determined by qPCR at E13 to examine whether the observed alterations had an earlier onset at mid-gestation. Structural analyses were performed using immunofluorescent staining against Ki67 and CD31 to investigate phenotypic outcomes at both timepoints. RESULTS: RNA-seq and IPA analyses revealed differential expression of transcripts and pathway interactions related to placental vascular development and tissue morphology in obese placentae at term, including downregulation of Muc15, Cnn1, and Acta2. Pdgfb, which is implicated in labyrinthine layer development, was downregulated in obese placentae at E13. This was consistent with the morphological evidence of reduced labyrinth zone (LZ) size, as well as lower fetal weight at both timepoints irrespective of offspring sex. CONCLUSIONS: Maternal obesity results in abnormal placental LZ development and impaired vascularization, which may mediate the observed FGR through reduced transfer of nutrients across the placenta.


Assuntos
Retardo do Crescimento Fetal , Obesidade Materna , Placenta , Transcriptoma/genética , Animais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade Materna/genética , Obesidade Materna/metabolismo , Placenta/metabolismo , Placenta/patologia , Gravidez
10.
FASEB J ; 33(6): 7758-7766, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30888848

RESUMO

Chronic fetal hypoxia is a common complication observed in human pregnancy, impacting pregnancies across global contexts. Exposure to chronic intrauterine hypoxia has major short- and long-term consequences for offspring health. However, the impact of chronic gestational hypoxia on female reproductive system development is unknown. We aimed to understand the impact of exposure to chronic fetal hypoxia on the developing female reproductive system. Wistar rat dams underwent normoxia (21%) or hypoxia (13%) during pregnancy. Postnatally, all female offspring were maintained in normoxic conditions into early adulthood. Female rats exposed to chronic gestational hypoxia (13%) during their intrauterine development had decreased ovarian primordial follicular reserve compared to controls (P < 0.05). Adult females who had been exposed to chronic fetal hypoxia had significantly reduced somatic ovarian telomere length (P < 0.05) and reduced ovarian protein expression of KU70, a critical component of the DNA-activated protein kinase repair complex (P < 0.01). Gene expression of NADPH oxidase 2-mediated oxidative stress markers was increased (P < 0.05). Exposure to chronic hypoxia during fetal development leads to accelerated aging of the somatic ovary and decreased ovarian reserve in adulthood. Ovarian aging is highly sensitive to gestational hypoxia, with implications for future fertility in next-generation offspring of high-risk pregnancies.-Aiken, C. E., Tarry-Adkins, J. L., Spiroski, A.-M., Nuzzo, A. M., Ashmore, T. J., Rolfo, A., Sutherland, M. J., Camm, E. J., Giussani, D. A., Ozanne, S. E. Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next-generation adult rats.


Assuntos
Hipóxia/fisiopatologia , Reserva Ovariana , Ovário/fisiopatologia , Envelhecimento , Animais , Doença Crônica , Feminino , Expressão Gênica , Gravidez , Ratos , Ratos Wistar
11.
J Physiol ; 597(9): 2391-2401, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30791124

RESUMO

KEY POINTS: Exposure to chronic hypoxia during gestation influences long-term health and development, including reproductive capacity, across generations. If the peri-conceptual environment in the developing oviduct is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations. In the present study, we show that the oviducts of female rats exposed to chronic hypoxia in utero have reduced telomere length, decreased mitochondrial DNA biogenesis and increased oxidative stress The results of the present study show that exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in early adulthood and they help us understand how exposure to hypoxia during development could influence reproductive health across generations. ABSTRACT: Exposure to chronic hypoxia during fetal development has important effects on immediate and long-term outcomes in offspring. Adverse impacts in adult offspring include impairment of cardiovascular function, metabolic derangement and accelerated ovarian ageing. However, it is not known whether other aspects of the female reproductive system may be similarly affected. In the present study, we examined the impact of chronic gestational hypoxia on the developing oviduct. Wistar rat dams were randomized to either normoxia (21%) or hypoxia (13%) from day 6 post-mating until delivery. Post-delivery female offspring were maintained in normoxia until 4 months of age. Oviductal gene expression was assayed at the RNA (quantitative RT-PCR) and protein (western blotting) levels. Oviductal telomere length was assayed using Southern blotting. Oviductal telomere length was reduced in the gestational hypoxia-exposed animals compared to normoxic controls (P < 0.01). This was associated with a specific post-transcriptional reduction in the KU70 subunit of DNA-pk in the gestational hypoxia-exposed group (P < 0.05). Gestational hypoxia-exposed oviducts also showed evidence of decreased mitochondrial DNA biogenesis, reduced mtDNA copy number (P < 0.05) and reduced gene expression of Tfam (P < 0.05) and Pgc1α (P < 0.05). In the hypoxia-exposed oviducts, there was upregulation of mitochondrial-specific anti-oxidant defence enzymes (MnSOD; P < 0.01). Exposure to chronic gestational hypoxia leads to accelerated ageing of the oviduct in adulthood. The oviduct plays a central role in early development as the site of gamete transport, syngamy, and early development; hence, accelerated ageing of the oviductal environment could have important implications for fertility and the health of future generations.


Assuntos
Hipóxia Fetal/fisiopatologia , Infertilidade/etiologia , Oviductos/metabolismo , Animais , DNA Mitocondrial/genética , Epigênese Genética , Feminino , Fertilidade , Hipóxia Fetal/complicações , Hipóxia Fetal/genética , Hipóxia Fetal/metabolismo , Oviductos/patologia , Estresse Oxidativo , Ratos , Ratos Wistar , Homeostase do Telômero , Transcriptoma
12.
FASEB J ; 33(1): 239-253, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29975569

RESUMO

Reduced fetal nutrition and rapid postnatal growth accelerates the aging phenotype in many organ systems; however, effects on the immune system are unclear. We addressed this by studying the thymus from a rat model of developmental programming. The recuperated group was generated by in utero protein restriction, followed by cross-fostering to control-fed mothers, and were then compared with controls. Fat infiltration and adipocyte size increased with age ( P < 0.001) and in recuperated thymi ( P < 0.05). Cortex/medulla ratio decreased with age ( P < 0.001) and decreased ( P < 0.05) in 12-mo recuperated thymi. Age-associated decreases in thymic-epithelial cell ( P < 0.01) and thymocyte markers ( P < 0.01) were observed in both groups and was decreased ( P < 0.05) in recuperated thymi. These data demonstrate effects of developmental programming upon thymic involution. The recuperated group had longer thymic telomeres than controls ( P < 0.001) at 22 d and at 3 mo, which was associated with increased expression of telomere-length maintenance molecules [telomerase RNA component ( Terc; P < 0.01), P23 ( P = 0.02), and Ku70 and Ku80 ( P < 0.01)]. By 12 mo, recuperated offspring had shorter thymic telomeres than controls had ( P < 0.001) and reduced DNA damage-response markers [( DNA-PKcs, Mre11 ( P < 0.01), Xrcc4 ( P = 0.02), and γ-H2ax ( P < 0.001], suggesting failure of earlier compensatory responses. Our results suggest that low birth weight with rapid postnatal growth results in premature thymic maturation, resulting in accelerated thymic aging. This could lead to increased age-associated vulnerability to infection.-Tarry-Adkins, J. L., Aiken, C. E., Ashmore, T. J., Fernandez-Twinn, D. S., Chen, J.-H., Ozanne, S. E. A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats.


Assuntos
Envelhecimento/patologia , Senescência Celular , Dieta , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Encurtamento do Telômero , Timo/patologia , Envelhecimento/metabolismo , Animais , Biomarcadores , Dano ao DNA , Feminino , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Timo/metabolismo
13.
Hypertension ; 72(4): 971-978, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354714

RESUMO

Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment (30 mg kg-1 d-1). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the ß1-adrenergic receptor, the M2 Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca2+ ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dtmax, +41.6%), reduced coronary flow rate (-21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery -19.1%; all P<0.05). Increased sympathetic reactivity (heart rate, +755.5%; left ventricular diastolic pressure, +418.9%) contributed to the enhanced myocardial contractility ( P<0.05). Perfusate CK (+431%) and LDH (+251.3%) and the cardiac expression of SERCA2a (+71.4%) were also elevated ( P<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase-derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.


Assuntos
Alopurinol/farmacologia , Insuficiência Cardíaca , Hipóxia , Contração Miocárdica/fisiologia , Complicações na Gravidez , Sistema Nervoso Simpático , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Testes de Função Cardíaca , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Masculino , Estresse Oxidativo , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Ratos , Receptor Muscarínico M2/metabolismo , Receptores Adrenérgicos beta/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Xantina Oxidase/antagonistas & inibidores
14.
Am J Pathol ; 188(12): 2704-2716, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30248337

RESUMO

The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. Early-onset hypoxia effects on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minimized. We further established whether maternal treatment with a mitochondria-targeted antioxidant (MitoQ) confers protection during hypoxic pregnancy. Wistar dams were exposed to normoxia (21% O2) or hypoxia (13% to 14% O2) from days 6 to 20 of pregnancy with and without MitoQ treatment (500 µmol/L in drinking water). On day 20, animals were euthanized and weighed, and the placentas from male fetuses were processed for stereology to assess morphology. UPR activation in additional cohorts of frozen placentas was determined with Western blot analysis. Neither hypoxic pregnancy nor MitoQ treatment affected fetal growth. Hypoxia increased placental volume and the fetal capillary surface area and induced mitochondrial stress as well as the UPR, as evidenced by glucose-regulated protein 78 and activating transcription factor (ATF) 4 protein up-regulation. MitoQ treatment in hypoxic pregnancy increased placental maternal blood space surface area and volume and prevented the activation of mitochondrial stress and the ATF4 pathway. The data suggest that mitochondria-targeted antioxidants may be beneficial in complicated pregnancy via mechanisms protecting against placental stress and enhancing placental perfusion.


Assuntos
Adaptação Fisiológica , Antioxidantes/farmacologia , Retardo do Crescimento Fetal/tratamento farmacológico , Hipóxia/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Placenta/fisiologia , Animais , Feminino , Retardo do Crescimento Fetal/metabolismo , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Placenta/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Resposta a Proteínas não Dobradas
15.
Cardiovasc Res ; 114(10): 1372-1384, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635288

RESUMO

Aims: Obesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac structure and function using an established mouse model of maternal diet-induced obesity. Methods and results: The impact of the maternal and postnatal environment on the offspring metabolic profile, arterial blood pressure, cardiac structure, and function was assessed in 8-week-old C57BL/6 male mice. Measurement of cardiomyocyte cell area, the transcriptional re-activation of cardiac fetal genes as well as genes involved in the regulation of contractile function and matrix remodelling in the adult heart were determined as potential mediators of effects on cardiac function. In the adult offspring: a post-weaning obesogenic diet coupled with exposure to maternal obesity increased serum insulin (P < 0.0001) and leptin levels (P < 0.0001); maternal obesity (P = 0.001) and a post-weaning obesogenic diet (P = 0.002) increased absolute heart weight; maternal obesity (P = 0.01) and offspring obesity (P = 0.01) caused cardiac dysfunction but effects were not additive; cardiac dysfunction resulting from maternal obesity was associated with re-expression of cardiac fetal genes (Myh7: Myh6 ratio; P = 0.0004), however, these genes were not affected by offspring diet; maternal obesity (P = 0.02); and offspring obesity (P = 0.05) caused hypertension and effects were additive. Conclusions: Maternal diet-induced obesity and offspring obesity independently promote cardiac dysfunction and hypertension in adult male progeny. Exposure to maternal obesity alone programmed cardiac dysfunction, associated with hallmarks of pathological left ventricular hypertrophy, including increased cardiomyocyte area, upregulation of fetal genes, and remodelling of cardiac structure. These data highlight that the perinatal period is just as important as adult-onset obesity in predicting CVD risk. Therefore, early developmental periods are key intervention windows to reduce the prevalence of CVD.


Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Cardiopatias/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Contração Miocárdica , Obesidade/complicações , Efeitos Tardios da Exposição Pré-Natal , Função Ventricular Esquerda , Remodelação Ventricular , Fatores Etários , Animais , Modelos Animais de Doenças , Feminino , Ganho de Peso na Gestação , Cardiopatias/sangue , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estado Nutricional , Obesidade/sangue , Obesidade/fisiopatologia , Gravidez
16.
Sci Rep ; 8(1): 4014, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29507362

RESUMO

Developmental programming phenotypes can be recapitulated in subsequent generations not directly exposed to the initial suboptimal intrauterine environment. A maternal low-protein diet during pregnancy and postnatal catch-up growth ('recuperated') alters insulin signaling and inflammation in rat offspring (F1-generation). We aimed to establish if this phenotype is also present in F2-generation females. Insulin-receptor-substrate-1 protein expression was decreased in para-ovarian adipose tissue at 3 months in offspring exposed to a grand-maternal low-protein diet (F2-recuperated), vs. F2-control animals (p < 0.05). There was no effect of grand-maternal diet upon Insulin-receptor-substrate-1 mRNA. Protein-kinase C-zeta protein levels were increased at 3 and 6 months in F2-recuperated animals (p < 0.01 at both ages). Phosphorylated-Aktser473 levels were decreased in F2-recuperated animals (p < 0.001). Interleukin-1ß protein levels were increased at 3 (p < 0.01) and (p < 0.001) 6 months in F2-recuperated animals. Vastus-lateralis insulin-receptor-ß protein expression (p < 0.001) and pAktser473 (p < 0.01) were increased at 3 months in F2-recuperated animals compared to controls. At 6 months, PAktser473 was lower in F2-recuperated animals (p < 0.001). Aspects of insulin signalling dysregulation and inflammation present in offspring of low-protein fed dams can be transmitted to subsequent generations without further exposure to a suboptimal maternal diet. These findings contribute to our understanding of insulin-resistance in grandchildren of sub-optimally nourished individuals during pregnancy.


Assuntos
Inflamação/metabolismo , Insulina/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Transdução de Sinais , Animais , Glicemia/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Insulina/sangue , Resistência à Insulina , Modelos Animais , Músculo Esquelético/metabolismo , Gravidez , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...