RESUMO
Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.
Assuntos
Acetilcisteína , Epigênese Genética , Retardo do Crescimento Fetal , Sulfeto de Hidrogênio , Hipóxia , Animais , Sulfeto de Hidrogênio/metabolismo , Acetilcisteína/farmacologia , Embrião de Galinha , Humanos , Feminino , Gravidez , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/fisiopatologia , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Metilação de DNA , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Vasodilatação/efeitos dos fármacos , Placenta/metabolismo , Placenta/irrigação sanguínea , Artérias Umbilicais/metabolismoRESUMO
The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland persists postnatally. We suggest that the male ovine mammary gland constitutes a promising adjunctive model for the male breast. In this study, we evaluate the male ovine mammary gland microenvironment, comparing intact and neutered males. Assessment of the glandular histo-anatomy highlights the resemblance of the male gland to that of neonatal female sheep and confirms the presence of rudimentary terminal duct lobular units. Irrespective of neutered status, cell proliferation in epithelial and stromal compartments is similarly low in males, and cell proliferation in epithelial cells and in the intralobular stroma is significantly lower than in pubertal female sheep. Between 42% and 72% of the luminal mammary epithelial cells in the male gland express the androgen receptor and expression is significantly reduced by neutering. Luminal epithelial cells within the intact and neutered male gland also express oestrogen receptor alpha, but minimal progesterone receptor expression is observed. The distribution of leukocytes within the ducts and stroma is similar to the mammary gland of female sheep and females of other species. Both macrophages and T lymphocytes are intercalated in the epithelial bilayer and are more abundant in the intralobular stroma than the interlobular stroma, suggesting that they may have a protective immunological function within the vestigial glandular tissue of the male sheep. Mast cells are also observed within the stroma. These cells cluster near the glandular tissue and are frequently located adjacent to blood vessels. The abundance of mast cells is significantly higher in intact males compared to neutered males, suggesting that hormone signalling may impact mast cell recruitment. In this study, we demonstrate the utility of the male ovine mammary gland as a model for furthering our knowledge of postnatal male mammary biology.
Assuntos
Glândulas Mamárias Animais , Animais , Masculino , Glândulas Mamárias Animais/anatomia & histologia , Glândulas Mamárias Animais/metabolismo , Ovinos , Modelos Animais , Feminino , Proliferação de Células/fisiologia , Células Epiteliais/metabolismoRESUMO
High-altitude pregnancy increases the incidence of fetal growth restriction and reduces birth weight. This poses a significant clinical challenge as both are linked to adverse health outcomes, including raised infant mortality and the development of the metabolic syndrome in later life. While this reduction in birth weight is mostly understood to be driven by the hypobaric hypoxia of high altitude, the causative mechanism is unclear. Moreover, it is now recognized that highland ancestry confers protection against this reduction in birth weight. Here, we analyze the evidence that pregnancy at high altitude reduces birth weight and that highland ancestry confers protection, discussing mechanisms contributing to both effects.
RESUMO
Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the United States. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand disease-related pathology. Significant systemic and cardiovascular physiological changes occur during pregnancy that are essential for supporting the maternal-fetal dyad. The physiological impact of pregnancy on the cardiovascular system has been examined in both experimental animal models and in humans. However, there is a continued need in this field of study to provide increased rigor and reproducibility. Therefore, these guidelines aim to provide information regarding best practices and recommendations to accurately and rigorously measure cardiovascular physiology during normal and cardiovascular disease-complicated pregnancies in human and animal models.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Período Pós-Parto , Gravidez , Humanos , Feminino , Animais , Complicações Cardiovasculares na Gravidez/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/diagnósticoRESUMO
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 â¼22 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/metabolismoRESUMO
OBJECTIVE: We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. METHODS: Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring cardiac miRNA expression and release. RESULTS: miR-15b-5p levels were increased in the sera of males born to mothers with higher BMI and in the hearts of adult mice born to obese dams. In an ex-vivo model of perfused mouse hearts, we demonstrated that cardiac tissue releases miR-15b-5p, and that some of the released miR-15b-5p was contained within small extracellular vesicles (EVs). We also demonstrated that release was higher from hearts exposed to maternal obesity following ischaemia/reperfusion. Over-expression of miR-15b-5p in vitro led to loss of outer mitochondrial membrane stability and to repressed fatty acid oxidation in cardiomyocytes. CONCLUSIONS: These findings suggest that miR-15-b could play a mechanistic role in the dysregulation of cardiac metabolism following exposure to an in utero obesogenic environment and that its release in cardiac EVs following ischaemic damage may be a novel factor contributing to inter-organ communication between the programmed heart and peripheral tissues.
Assuntos
Doenças Cardiovasculares , Vesículas Extracelulares , MicroRNAs , Obesidade Materna , Traumatismo por Reperfusão , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Gravidez , Doenças Cardiovasculares/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade Materna/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. However, whether antenatal antioxidant therapy confers any benefit on lung development in complicated pregnancies has not yet been investigated. Here, we tested the hypothesis that maternal antenatal treatment with MitoQ will protect the developing lung in hypoxic pregnancy in sheep, a species with similar fetal lung developmental milestones as humans. Maternal treatment with MitoQ during late gestation promoted fetal pulmonary surfactant maturation and an increase in the expression of lung mitochondrial complexes III and V independent of oxygenation. Maternal treatment with MitoQ in hypoxic pregnancy also increased the expression of genes regulating liquid reabsorption in the fetal lung. These data support the hypothesis tested and suggest that MitoQ as an antenatal targeted antioxidant treatment may improve lung maturation in the late gestation fetus. KEY POINTS: Chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascular development. MitoQ is a targeted antioxidant that uses the cell and the mitochondrial membrane potential to accumulate within the mitochondria. Treatment of healthy or hypoxic pregnancy with MitoQ, increases the expression of key molecules involved in surfactant maturation, lung liquid reabsorption and in mitochondrial proteins driving ATP synthesis in the fetal sheep lung. There were no detrimental effects of MitoQ treatment alone on the molecular components measured in the present study, suggesting that maternal antioxidant treatment has no effect on other components of normal maturation of the surfactant system.
Assuntos
Antioxidantes , Hipóxia , Compostos Organofosforados , Ubiquinona/análogos & derivados , Humanos , Recém-Nascido , Gravidez , Feminino , Animais , Ovinos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Pulmão/fisiologia , Tensoativos/metabolismo , Tensoativos/farmacologiaRESUMO
Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off-target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg-1 ), Beta (0.1 mg kg-1 ), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO-dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin-1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.
Assuntos
Betametasona , Glucocorticoides , Embrião de Galinha , Feminino , Gravidez , Animais , Betametasona/efeitos adversos , Glucocorticoides/efeitos adversos , Coração , Artérias , Dexametasona/efeitos adversosRESUMO
BACKGROUND: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. METHODS: We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. RESULTS: We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. CONCLUSIONS: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Nascimento Prematuro , Recém-Nascido , Humanos , Feminino , Glucocorticoides/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Nascimento Prematuro/prevenção & controle , Anti-Inflamatórios , Recém-Nascido Prematuro , DexametasonaRESUMO
Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies.
Assuntos
Placenta , Complicações na Gravidez , Humanos , Gravidez , Feminino , Masculino , Ratos , Animais , Placenta/metabolismo , Roedores , Caracteres Sexuais , Resultado da Gravidez , Retardo do Crescimento Fetal/metabolismo , Resposta a Proteínas não Dobradas , Complicações na Gravidez/metabolismo , Hipóxia/metabolismoRESUMO
BACKGROUND: Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short-term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. OBJECTIVES: To systematically review the human clinical literature to determine the effects of ACS on offspring cardiovascular function. SEARCH STRATEGY: A systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE, EMBASE and Cochrane databases. SELECTION CRITERIA: Offspring who had been exposed to ACS during fetal life, in comparison with those not receiving steroids, those receiving a placebo or population data, were included. Studies not performed in humans or that did not assess cardiovascular function were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently screened the studies, extracted the data and assessed the quality of the studies. Results were combined descriptively and analysed using a standardised Excel form. MAIN RESULTS: Twenty-six studies including 1921 patients were included, most of which were cohort studies of mixed quality. The type of ACS exposure, gestational age at exposure, dose and number of administrations varied widely. Offspring cardiovascular outcomes were assessed from 1 day to 36 years postnatally. The most commonly assessed parameter was arterial blood pressure (18 studies), followed by echocardiography (eight studies), heart rate (five studies), electrocardiogram (ECG, three studies) and cardiac magnetic resonance imaging (MRI, one study). There were no clinically significant effects of ACS exposure on offspring blood pressure. However, there were insufficient studies assessing cardiac structure and function using echocardiography or cardiac MRI to be able to determine an effect. CONCLUSIONS: The administration of ACS is not associated with long-term effects on blood pressure in exposed human offspring. The effects on cardiac structure and other measures of cardiac function were unclear because of the small number, heterogeneity and mixed quality of the studies. Given the preclinical and human evidence of potential harm following ACS exposure, there is a need for further research to assess central cardiac function in human offspring exposed to ACS.
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Corticosteroides , Cuidado Pré-Natal , Recém-Nascido , Humanos , Gravidez , Feminino , Cuidado Pré-Natal/métodos , Idade Gestacional , Desenvolvimento InfantilRESUMO
Developmental hypoxia has profound and persistent effects on the vertebrate cardiovascular system, but the nature, magnitude, and long-term outcome of the hypoxic consequences are species specific. Here we aim to identify common and novel cardiovascular responses among vertebrates that encounter developmental hypoxia, and we discuss the possible medical and ecological implications.
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Sistema Cardiovascular , Humanos , Animais , Vertebrados , Hipóxia , Coração/fisiologiaRESUMO
Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodeling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex-dependent manner. However, the functional effects of these modifications on mitochondrial respiration remain unknown. Furthermore, while maternal antioxidant treatments are emerging as a promising new strategy to protect the hypoxic fetus, whether these treatments convey similar protection to cardiac mitochondria in the male or female fetus has not been investigated. Therefore, using an established rat model, we measured the sex-dependent effects of gestational hypoxia and maternal melatonin treatment on fetal cardiac mitochondrial respiration, reactive oxygen species (ROS) production, and lipid peroxidation. Pregnant Wistar rats were subjected to normoxia or hypoxia (13% oxygen) during gestational days (GDs) 6-20 (term ~22 days) with or without melatonin treatment (5 µg/ml in maternal drinking water). On GD 20, mitochondrial aerobic respiration and H2 O2 production were measured in fetal heart tissue, together with lipid peroxidation and citrate synthase (CS) activity. Gestational hypoxia reduced maternal body weight gain (p < .01) and increased placental weight (p < .05) but had no effect on fetal weight or litter size. Cardiac mitochondria from male but not female fetuses of hypoxic pregnancy had reduced respiratory capacity at Complex II (CII) (p < .05), and an increase in H2 O2 production/O2 consumption (p < .05) without any changes in lipid peroxidation. CS activity was also unchanged in both sexes. Despite maternal melatonin treatment increasing maternal and fetal plasma melatonin concentration (p < .001), melatonin treatment had no effect on any of the mitochondrial parameters investigated. To conclude, we show that gestational hypoxia leads to ROS generation from the mitochondrial electron transport chain and affects fetal cardiac mitochondrial respiration in a sex-dependent manner. We also show that maternal melatonin treatment had no effect on these relationships, which has implications for the development of future therapies for hypoxic pregnancies.
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Melatonina , Animais , Feminino , Coração Fetal/metabolismo , Hipóxia/metabolismo , Masculino , Melatonina/metabolismo , Melatonina/farmacologia , Mitocôndrias Cardíacas/metabolismo , Estresse Oxidativo , Oxigênio/metabolismo , Oxigênio/farmacologia , Placenta , Gravidez , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common downstream pathways of cell stress, and there is evidence that this conserved homeostatic response may be a key mediator in the pathogenesis of placental dysfunction. We summarize the current literature on the placental cellular and molecular changes that occur in obese women. A special focus is cast onto placental ER stress in obese pregnancy, which may provide a novel link for future investigation.
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Obesidade Materna , Placenta , Estresse do Retículo Endoplasmático , Feminino , Humanos , Obesidade/metabolismo , Placenta/metabolismo , Gravidez , Resposta a Proteínas não DobradasRESUMO
BACKGROUND: Preeclampsia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preeclampsia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology. METHODS: We adopted an integrative approach to investigate the inter-relationship between chronic hypoxia during pregnancy with maternal, placental, and fetal outcomes, common in preeclampsia. We exploited a novel technique using isobaric hypoxic chambers and in vivo continuous cardiovascular recording technology for measurement of blood pressure in sheep and studied the placental stress in response to hypoxia at cellular and subcellular levels. RESULTS: Chronic hypoxia in ovine pregnancy promoted fetal growth restriction (FGR) with evidence of fetal brain-sparing, increased placental hypoxia-mediated oxidative damage, and activated placental stress response pathways. These changes were linked with dilation of the placental endoplasmic reticulum (ER) cisternae and increased placental expression of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), combined with a shift towards an angiogenic imbalance in the maternal circulation. Chronic hypoxia further led to an increase in uteroplacental vascular resistance and the fall in maternal blood pressure with advancing gestation measured in normoxic pregnancy did not occur in hypoxic pregnancy. CONCLUSIONS: Therefore, we show in an ovine model of sea-level adverse pregnancy that chronic hypoxia recapitulates physiological and molecular features of preeclampsia in the mother, placenta, and offspring.
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Pré-Eclâmpsia , Animais , Biomarcadores/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Mães , Placenta/metabolismo , Fator de Crescimento Placentário , Gravidez , Ovinos , Receptor 1 de Fatores de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whether preeclampsia with or without fetal growth restriction exaggerated fetal hypoxia and impaired angiogenesis in the fetal lung, leading to neonatal cardiopulmonary circulation abnormalities and neonatal or infantile PH. METHODS AND RESULTS: We studied 79 maternal-infant pairs (39 preeclampsia, 40 controls) in Bolivia (3600-4100 m). Cord blood erythropoietin, hemoglobin, and umbilical artery and venous blood gases were measured as indices of fetal hypoxia. Maternal and cord plasma levels of angiogenic (VEGF [vascular endothelial growth factor]) and antiangiogenic (sFlt1 [soluble fms-like tyrosine kinase]) factors were determined. Postnatal echocardiography (1 week and 6-9 months) assessed pulmonary hemodynamics and PH. Preeclampsia augmented fetal hypoxia and increased the risk of PH in the neonate but not later in infancy. Pulmonary abnormalities were confined to preeclampsia cases with fetal growth restriction. Maternal and fetal plasma sFlt1 levels were higher in preeclampsia than controls and positively associated with PH. CONCLUSIONS: The effect of preeclampsia with fetal growth restriction to increase fetal hypoxia and sFlt1 levels may impede normal development of the pulmonary circulation at high altitude, leading to adverse neonatal pulmonary vascular outcomes. Our observations highlight important temporal windows for the prevention of pulmonary vascular disease among babies born to highland residents or those with exaggerated hypoxia in utero or newborn life.
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Hipertensão Pulmonar , Pré-Eclâmpsia , Altitude , Feminino , Retardo do Crescimento Fetal , Hipóxia Fetal , Humanos , Hipertensão Pulmonar/etiologia , Recém-Nascido , Fator de Crescimento Placentário , Gravidez , Estudos Prospectivos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2 ) pregnancy ± melatonin (M) treatment (5 µg·ml-1 .day-1 ) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15-20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.
Assuntos
Melatonina , Complicações na Gravidez , Animais , Feminino , Retardo do Crescimento Fetal , Hipóxia , Melatonina/farmacologia , Gravidez , Ratos , Ratos WistarRESUMO
BACKGROUND: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. METHODS: We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105-138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. RESULTS: Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. CONCLUSIONS: Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. IMPACT: Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.
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Antioxidantes , Surfactantes Pulmonares , Adulto , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Feminino , Feto/metabolismo , Humanos , Pulmão , Gravidez , Surfactantes Pulmonares/metabolismo , Ovinos , TensoativosRESUMO
OBJECTIVE: To understand the relationship between birth weight and altitude to improve health outcomes in high-altitude populations, to systematically assess the impact of altitude on the likelihood of low birth weight (LBW), small for gestational age (SGA), and spontaneous preterm birth (sPTB), and to estimate the magnitude of reduced birth weight associated with altitude. METHODS: PubMed, OvidEMBASE, Cochrane Library, Medline, Web of Science, and clinicaltrials.gov were searched (from inception to November 11, 2020). Observational, cohort, or case-control studies were included if they reported a high altitude (>2500 m) and appropriate control population. RESULTS: Of 2524 studies identified, 59 were included (n = 1 604 770 pregnancies). Data were abstracted according to PRISMA guidelines, and were pooled using random-effects models. There are greater odds of LBW (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.33-1.62, P < 0.001), SGA (OR 1.88, 95% CI 1.08-3.28, P = 0.026), and sPTB (OR 1.23, 95% CI 1.04-1.47, P = 0.016) in high- versus low-altitude pregnancies. Birth weight decreases by 54.7 g (±13.0 g, P < 0.0001) per 1000 m increase in altitude. Average gestational age at delivery was not significantly different. CONCLUSION: Globally, the likelihood of adverse perinatal outcomes, including LBW, SGA, and sPTB, increases in high-altitude pregnancies. There is an inverse relationship between birth weight and altitude. These findings have important implications for the increasing global population living at altitudes above 2500 m.