Hypoxia, AMPK activation and uterine artery vasoreactivity

Skeffington, Katie L.; Higgins, J. Nicholas P.; Mahmoud, Amira D.; Evans, Allan M.; Sferruzzi‐Perri, Amanda N.; Fowden, Abigail L.; Yung, Hong Wa; Burton, Graham J.; Giussani, Dino A.; Moore, Lorna G.

doi:10.1113/jp270995

Cited by 52 publications

(56 citation statements)

References 65 publications

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“…Consistent with this, recent work has shown increased activation of the energy sensor, adenosine monophosphate‐activated protein kinase (AMPK), in the placenta and uterine vessels of mouse dams exposed to 10% O 2 hypoxia for the same period in pregnancy (Skeffington et al . ). Enhanced AMPK activation may prevent further energy depletion and optimize utero‐placental blood flow in the prevailing hypoxic environment.…”

Section: Discussionmentioning

confidence: 97%

Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Higgins

Vaughan

Liger

et al. 2015

The Journal of Physiology

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106

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Key points Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth.In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia.Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age.Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia.There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies. AbstractThe placenta adapts its transport capacity to nutritional cues developmentally, although relatively little is known about placental transport phenotype in response to hypoxia, a major cause of fetal growth restriction. The present study determined the effects of both moderate hypoxia (13% inspired O2) between days (D)11 and D16 or D14 and D19 of pregnancy and severe hypoxia (10% inspired O2) from D14 to D19 on placental morphology, transport capacity and fetal growth on D16 and D19 (term∼D20.5), relative to normoxic mice in 21% O2. Placental morphology adapted beneficially to 13% O2; fetal capillary volume increased at both ages, exchange area increased at D16 and exchange barrier thickness reduced at D19. Exposure to 13% O2 had no effect on placental nutrient transport on D16 but increased placental uptake and clearance of 3H‐methyl‐d‐glucose at D19. By contrast, 10% O2 impaired fetal vascularity, increased barrier thickness and reduced placental 14C‐methylaminoisobutyric acid clearance at D19. Consequently, fetal growth was only marginally affected in 13% O2 (unchanged at D16 and −5% at D19) but was severely restricted in 10% O2 (−21% at D19). The hypoxia‐induced changes in placental phenotype were accompanied by altered placental insulin‐like growth factor (IGF)‐2 expression and insulin/IGF signalling, as well as by maternal hypophagia depending on the timing and severity of the hypoxia. Overall, the present study shows that the mouse placenta can integrate signals of oxygen and nutrient availability, possibly through the insulin‐IGF pathway, to adapt its phenotype and optimize maternal resource allocation to fetal growth during late pregnancy. It also suggests that there is a threshold between 13% and 10% inspired O2 at which these adaptations no longer occur.

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Section: Discussionmentioning

confidence: 97%

Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Higgins

Vaughan

Liger

et al. 2015

The Journal of Physiology

Self Cite

106

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“…It has been shown that AMPK activation may play an adaptive role to maintain utero‐placental blood flow in a hypoxic pregnancy by causing vasodilatation of the uterine artery in a murine model (Skeffington et al . ), which signifies the protective role of AMPK during a hypoxic pregnancy. We have previously shown that resveratrol activates the AMPK–ACC axis in the liver tissue in both normoxia and prenatal hypoxia‐exposed male offspring (Dolinsky et al .…”

Section: Discussionmentioning

confidence: 97%

Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet

Shah

Reyes

Morton

et al. 2015

The Journal of Physiology

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Key pointsr Prenatal hypoxia, a common outcome of many pregnancy complications, predisposes offspring to chronic diseases in later life.r We investigated the effect of prenatal hypoxia, on a background of a high-fat diet, on metabolic and cardiac function in adult male and female rat offspring. We also examined the therapeutic role of resveratrol supplementation in preventing metabolic and cardiac dysfunction.r Prenatal hypoxia impaired both metabolic and cardiac function in male and only cardiac function in female rat offspring. We also observed that male rat offspring were more susceptible to metabolic and cardiac dysfunction as compared with their female counterparts; this provides evidence of sexual dichotomy in the fetal programming of diseases due to prenatal hypoxia.r Resveratrol supplementation in the diet improved metabolic and cardiac function independent of sex; this provides evidence of a possible therapeutic role of resveratrol in susceptible male and female rat offspring exposed to prenatal hypoxia.Abstract Prenatal hypoxia, a common outcome of pregnancy complications, predisposes offspring to the development of metabolic and cardiovascular disorders in later life. We have previously observed that resveratrol improved cardiovascular and metabolic health in adult male rat offspring exposed to prenatal hypoxia and a postnatal high-fat (HF) diet; however, the effects of resveratrol in female rat offspring are not known. Our aim was to identify the mechanism(s) by which resveratrol may prevent metabolic and cardiac dysfunction in both male and female rat offspring exposed to prenatal hypoxia and a postnatal HF diet. Offspring that experienced normoxia or hypoxia in utero were fed a HF diet or a HF diet supplemented with resveratrol for 9 weeks following weaning. Body composition, metabolic function, in vivo cardiac function and ex vivo cardiac susceptibility to ischaemia-reperfusion (I/R) injury were assessed at 12 weeks of age. Prenatal hypoxia impaired metabolic function in male, but not female, rat offspring fed a HF diet and this was improved by resveratrol supplementation. Prenatal hypoxia also led to reduced recovery from cardiac I/R injury in male, and to a lesser extent in female, rat offspring fed a HF diet. Indices of cardiac oxidative stress after I/R were enhanced in both male and female rat offspring exposed to prenatal hypoxia. Resveratrol improved cardiac recovery from I/R injury and attenuated superoxide levels in both male and female rat offspring. In conclusion, prenatal hypoxia impaired metabolic and cardiac function in a sex-specific manner. Resveratrol supplementation may improve metabolic and cardiovascular health in adult male and female rat offspring exposed to prenatal hypoxia.

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“…Human pregnancies at high altitude are a natural experimental model to study chronic hypoxia and IUGR. These studies have focused on placenta function and nutrient delivery and found decreased glucose transport and delivery to the fetus (Illsley et al, 2010, Skeffington et al, 2015, Zamudio et al, 2010), similar to the reduced glucose uptake found in the IUGR sheep fetus (Limesand et al, 2007, Thureen et al, 1992). …”

Section: Mechanisms For the Early Activation Of Fetal Hgp In The Imentioning

confidence: 87%

Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

Wesolowski

Hay

2016

Molecular and Cellular Endocrinology

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Glucose is the major fuel for fetal oxidative metabolism. A positive maternal-fetal glucose gradient drives glucose across the placenta and is sufficient to meet the demands of the fetus, eliminating the need for endogenous hepatic glucose production (HGP). However, fetuses with intrauterine growth restriction (IUGR) from pregnancies complicated by placental insufficiency have an early activation of HGP. Furthermore, this activated HGP is resistant to suppression by insulin. Here, we present the data demonstrating the activation of HGP in animal models, mostly fetal sheep, and human pregnancies with IUGR. We also discuss potential mechanisms and pathways that may produce and support HGP and hepatic insulin resistance in IUGR fetuses.

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Hypoxia, AMPK activation and uterine artery vasoreactivity

Cited by 52 publications

References 65 publications

Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Effect of resveratrol on metabolic and cardiovascular function in male and female adult offspring exposed to prenatal hypoxia and a high‐fat diet

Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

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