Relation between damage to the placenta and the fetal brain after late-gestation placental embolization and fetal growth restriction in sheep

Background: Maternal malnutrition can lead to fetal growth restriction. This is often associated with organ sparing and long-lasting physiological dysfunctions during adulthood, although the underlying mechanisms are not yet well understood. Methods: Low protein (LP) dietary models in C57BL/6J mice were used to investigate the proximal effects of maternal malnutrition on fetal organ weights and organ sparing at embryonic day 18.5 (E18.5). Results: Maternal 8% LP diet induced strikingly different degrees of fetal growth restriction in different animal facilities, but adjustment of dietary protein content allowed similar fetal body masses to be obtained. A maternal LP diet that restricted fetal body mass by 40% did not decrease fetal brain mass to the same extent, reflecting positive growth sparing of this organ. Under these conditions, fetal pancreas and liver mass decreased by 60-70%, indicative of negative organ sparing. A series of dietary swaps between LP and standard diets showed that the liver is capable of efficient catch-up growth from as late as E14.5 whereas, after E10.5, the pancreas is not. Conclusions: This study highlights that the reproducibility of LP fetal growth restriction studies between laboratories can be improved by careful calibration of maternal dietary protein content. LP diets that induce 30-40% restriction of prenatal growth provide a good model for fetal organ sparing. For the liver, recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit.

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OP17.08: Assessment of fetal brain volume by tridimensional ultrasound in fetal growth restriction

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.11554 ◽

2012 ◽

Vol 40 (S1) ◽

pp. 107-107

Author(s):

A. R. Caetano ◽

A. P. Zamarian ◽

R. Cavalcante ◽

D. Soares ◽

P. M. Nowak ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Brain Volume ◽

Fetal Brain ◽

Growth Restriction

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Altered neurodevelopmental DNA methylation status after fetal growth restriction with brain-sparing

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174421000374 ◽

2021 ◽

pp. 1-12

Author(s):

Anne E. Richter ◽

Iris Bekkering-Bauer ◽

Rikst Nynke Verkaik-Schakel ◽

Mariëtte Leeuwerke ◽

Jozien C. Tanis ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Child Behavior Checklist ◽

Epigenetic Modification ◽

Methylation Status ◽

Neurodevelopmental Outcome ◽

Fetal Brain ◽

Growth Restriction ◽

Tyrosine Kinase Receptor ◽

Response Element

Abstract It is under debate how preferential perfusion of the brain (brain-sparing) in fetal growth restriction (FGR) relates to long-term neurodevelopmental outcome. Epigenetic modification of neurotrophic genes by altered fetal oxygenation may be involved. To explore this theory, we performed a follow-up study of 21 FGR children, in whom we prospectively measured the prenatal cerebroplacental ratio (CPR) with Doppler sonography. At 4 years of age, we tested their neurodevelopmental outcome using the Wechsler Preschool and Primary Scale of Intelligence, the Child Behavior Checklist, and the Behavior Rating Inventory of Executive Function. In addition, we collected their buccal DNA to determine the methylation status at predefined genetic regions within the genes hypoxia-inducible factor-1 alpha (HIF1A), vascular endothelial growth factor A (VEGFA), erythropoietin (EPO), EPO-receptor (EPOR), brain-derived neurotrophic factor (BDNF), and neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) by pyrosequencing. We found that FGR children with fetal brain-sparing (CPR <1, n = 8) demonstrated a trend (0.05 < p < 0.1) toward hypermethylation of HIF1A and VEGFA at their hypoxia-response element (HRE) compared with FGR children without fetal brain-sparing. Moreover, in cases with fetal brain-sparing, we observed statistically significant hypermethylation at a binding site for cyclic adenosine monophophate response element binding protein (CREB) of BDNF promoter exon 4 and hypomethylation at an HRE located within the NTRK2 promoter (both p <0.05). Hypermethylation of VEGFA was associated with a poorer Performance Intelligence Quotient, while hypermethylation of BDNF was associated with better inhibitory self-control (both p <0.05). These results led us to formulate the hypothesis that early oxygen-dependent epigenetic alterations due to hemodynamic alterations in FGR may be associated with altered neurodevelopmental outcome in later life. We recommend further studies to test this hypothesis.

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EP19.09: Assessment of fetal brain vascularisation in fetal growth restriction comparing 3D power angiography to 2D velocimetry

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.21511 ◽

2019 ◽

Vol 54 (S1) ◽

pp. 353-354

Author(s):

A. Rossi ◽

C. Braghin ◽

A. Azzena

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Fetal Brain ◽

Growth Restriction

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The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00379.2015 ◽

2016 ◽

Vol 310 (1) ◽

pp. E24-E31 ◽

Cited By ~ 6

Author(s):

Jayne C. Charnock ◽

Mark R. Dilworth ◽

John D. Aplin ◽

Colin P. Sibley ◽

Melissa Westwood ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Mixed Model ◽

Maternal Serum ◽

Growth Restriction ◽

Placental Weight ◽

Late Gestation ◽

Fetal Weight ◽

Mixed Model Analysis ◽

The Impact

Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu27]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu27]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS−/−; FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg−1·day−1 [Leu27]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu27]IGF-II treatment halved the number of FGR fetuses, reduced fetal( P = 0.028) and placental weight variations ( P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu27]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu27]IGF-II-treated WT animals ( P < 0.01). In eNOS−/− mice, [Leu27]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS−/− litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring.

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Increased uterine artery blood flow in hypoxic murine pregnancy is not sufficient to prevent fetal growth restriction†

Biology of Reproduction ◽

10.1093/biolre/ioz208 ◽

2019 ◽

Vol 102 (3) ◽

pp. 660-670 ◽

Cited By ~ 2

Author(s):

Sydney L Lane ◽

Alexandrea S Doyle ◽

Elise S Bales ◽

Ramón A Lorca ◽

Colleen G Julian ◽

...

Keyword(s):

Blood Flow ◽

Fetal Growth ◽

Murine Model ◽

Pregnancy Complications ◽

Fetal Growth Restriction ◽

Uterine Artery ◽

Growth Restriction ◽

Late Gestation ◽

Artery Blood Flow ◽

Uterine Arteries

Abstract Incomplete maternal vascular responses to pregnancy contribute to pregnancy complications including intrauterine growth restriction (IUGR) and preeclampsia. We aimed to characterize maternal vascular dysfunction in a murine model of fetal growth restriction as an approach toward identifying targetable pathways for improving pregnancy outcomes. We utilized a murine model of late-gestation hypoxia-induced IUGR that reduced E18.5 fetal weight by 34%. Contrary to our hypothesis, uterine artery blood flow as measured in vivo by Doppler ultrasound was increased in mice housed under hypobaric hypoxia (385 mmHg; 5500 m) vs normoxia (760 mmHg; 0 m). Using wire myography, uterine arteries isolated from hypoxic mice had similar vasodilator responses to the two activators A769662 and acetylcholine as those from normoxic mice, although the contribution of an increase in nitric oxide production to uterine artery vasodilation was reduced in the hypoxic vs normoxic groups. Vasoconstrictor responses to phenylephrine and potassium chloride were unaltered by hypoxia. The levels of activated adenosine monophosphate-activated protein kinase (AMPK) were reduced with hypoxia in both the uterine artery and placenta as measured by western blot and immunohistochemistry. We concluded that the rise in uterine artery blood flow may be compensatory to hypoxia but was not sufficient to prevent fetal growth restriction. Although AMPK signaling was reduced by hypoxia, AMPK was still receptive to pharmacologic activation in the uterine arteries in which it was a potent vasodilator. Thus, AMPK activation may represent a new therapy for pregnancy complications involving reduced uteroplacental perfusion.

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