VP33.02: Comprehensive maternal and fetal hemodynamics assessed by cardiovascular MRI in a sheep model of late gestation maternal undernutrition

We have developed a sheep model to facilitate studies of the fetal programming effects of mismatched perinatal and postnatal nutrition. During the last trimester of gestation, twenty-one twin-bearing ewes were fed a normal diet fulfilling norms for energy and protein (NORM) or 50 % of a normal diet (LOW). From day 3 postpartum to 6 months (around puberty) of age, one twin lamb was fed a conventional (CONV) diet and the other a high-carbohydrate–high-fat (HCHF) diet, resulting in four groups of offspring: NORM-CONV; NORM-HCHF; LOW-CONV; LOW-HCHF. At 6 months of age, half of the lambs (all males and three females) were slaughtered for further examination and the other half (females only) were transferred to a moderate sheep diet until slaughtered at 24 months of age (adulthood). Maternal undernutrition during late gestation reduced the birth weight of LOW offspring (P< 0·05), and its long-term effects were increased adrenal size in male lambs and adult females (P< 0·05), increased neonatal appetite for fat-(P= 0·004) rather than carbohydrate-rich feeds (P< 0·001) and reduced deposition of subcutaneous fat in both sexes (P< 0·05). Furthermore, LOW-HCHF female lambs had markedly higher visceral:subcutaneous fat ratios compared with the other groups (P< 0·001). Postnatal overfeeding (HCHF) resulted in obesity (>30 % fat in soft tissue) and widespread ectopic lipid deposition. In conclusion, our sheep model revealed strong pre- and postnatal impacts on growth, food preferences and fat deposition patterns. The present findings support a role for subcutaneous adipose tissue in the development of visceral adiposity, which in humans is known to precede the development of the metabolic syndrome in human adults.

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Effects of maternal periconceptional undernutrition in sheep on offspring glucose–insulin axis function into adulthood

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420001063 ◽

2020 ◽

pp. 1-7

Author(s):

Mark H. Oliver ◽

Frank H. Bloomfield ◽

Amita Bansal ◽

Hui Hui Phua ◽

Eric B. Thorstensen ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Protein Expression ◽

Insulin Signalling ◽

Area Under The Curve ◽

Late Gestation ◽

Maternal Undernutrition ◽

Kinase C ◽

First Phase Insulin Secretion ◽

Protein Kinase C Zeta

Abstract Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15–20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7–10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%–58% in fetuses (P = 0.004), but decreased 39%–43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

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Serotonin contributes to high pulmonary vascular tone in a sheep model of persistent pulmonary hypertension of the newborn

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00043.2013 ◽

2013 ◽

Vol 304 (12) ◽

pp. L894-L901 ◽

Cited By ~ 25

Author(s):

Cassidy Delaney ◽

Jason Gien ◽

Gates Roe ◽

Nicole Isenberg ◽

Jenai Kailey ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Tryptophan Hydroxylase ◽

Late Gestation ◽

Persistent Pulmonary Hypertension ◽

Sheep Model ◽

Pulmonary Hemodynamics ◽

Fetal Sheep ◽

Pulmonary Arterial

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. We hypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increases PVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment ( P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment ( P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment ( P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model.

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EFFECTS OF MATERNAL NUTRITION ON THE HUMAN FETUS

PEDIATRICS ◽

10.1542/peds.52.4.494 ◽

1973 ◽

Vol 52 (4) ◽

pp. 494-503

Author(s):

Richard L. Naeye ◽

William Blanc ◽

Cheryl Paul

Keyword(s):

Body Weight ◽

Weight Gain ◽

Maternal Nutrition ◽

Cellular Growth ◽

Late Gestation ◽

Third Trimester ◽

Organ Growth ◽

Maternal Undernutrition ◽

The Third ◽

Body Organ

In a study of 467 gestations maternal stature had little correlation with fetal growth but mother's pregravid body weight as well as weight gain and low-calorie diets during pregnancy did have such a correlation. Maternal undernutrition before the third trimester had little or no influence on fetal body, organ, and cellular growth while such effects were pronounced in late gestation. Fetal body and organ growth improved with successive pregnancies except in the most poorly nourished mothers, whose successive neonates became more growth retarded.

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Maternal undernutrition induces fetal hepatic lipid metabolism disorder and affects the development of fetal liver in a sheep model

The FASEB Journal ◽

10.1096/fj.201900406r ◽

2019 ◽

Vol 33 (9) ◽

pp. 9990-10004 ◽

Cited By ~ 6

Author(s):

Yanfeng Xue ◽

Changzheng Guo ◽

Fan Hu ◽

Weiyun Zhu ◽

Shengyong Mao

Keyword(s):

Lipid Metabolism ◽

Fetal Liver ◽

Hepatic Lipid Metabolism ◽

Lipid Metabolism Disorder ◽

Sheep Model ◽

Hepatic Lipid ◽

Maternal Undernutrition ◽

Metabolism Disorder

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Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174413000378 ◽

2013 ◽

Vol 4 (5) ◽

pp. 391-401 ◽

Cited By ~ 8

Author(s):

S. Zhang ◽

O. Williams-Wyss ◽

S. M. MacLaughlin ◽

S. K. Walker ◽

D. O. Kleemann ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Mrna Expression ◽

Hpa Axis ◽

Early Embryo ◽

Late Gestation ◽

Control Group ◽

Fetal Sheep ◽

Maternal Undernutrition ◽

Stress Responsiveness ◽

Periconceptional Period

Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo–pituitary–adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of ‘periconceptional’ undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and ‘early preimplantation’ undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11β-hydroxysteroid dehydrogenase type 1 and 2 (11βHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136–138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11βHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.

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Insulin Deficiency Alters the Metabolic and Endocrine Responses to Undernutrition in Fetal Sheep Near Term

Endocrinology ◽

10.1210/en.2012-1063 ◽

2012 ◽

Vol 153 (8) ◽

pp. 4008-4018 ◽

Cited By ~ 5

Author(s):

Abigail L. Fowden ◽

Alison J. Forhead

Keyword(s):

Oxygen Consumption ◽

Metabolic Response ◽

Plasma Concentrations ◽

Late Gestation ◽

Similar Degree ◽

Hepatic Glycogen ◽

Insulin Deficiency ◽

Fetal Sheep ◽

Maternal Undernutrition ◽

Significant Fall

Insulin deficiency affects the adult metabolic response to undernutrition, but its effects on the fetal response to maternal undernutrition remain unknown. This study examined the effects of maternal fasting for 48 h in late gestation on the metabolism of fetal sheep made insulin deficient by pancreatectomy (PX). The endocrine and metabolic responses to maternal fasting differed between intact, sham-operated and PX fetuses, despite a similar degree of hypoglycemia. Compared with intact fetuses, there was no increase in the plasma concentrations of cortisol or norepinephrine in PX fetuses during maternal fasting. In contrast, there was a significant fasting-induced rise in plasma epinephrine concentrations in PX but not intact fetuses. Umbilical glucose uptake decreased to a similar extent in both groups of fasted animals but was associated with a significant fall in glucose carbon oxidation only in intact fetuses. Pancreatectomized but not intact fetuses lowered their oxygen consumption rate by 15–20% during maternal fasting in association with increased uteroplacental oxygen consumption. Distribution of uterine oxygen uptake between the uteroplacental and fetal tissues therefore differed with fasting only in PX fetuses. Both groups of fetuses produced glucose endogenously after maternal fasting for 48 h, which prevented any significant fall in the rate of fetal glucose utilization. In intact but not PX fetuses, fasting-induced glucogenesis was accompanied by a lower hepatic glycogen content. Chronic insulin deficiency in fetal sheep therefore leads to changes in the counterregulatory endocrine response to hypoglycemia and an altered metabolic strategy in dealing with nutrient restriction in utero.

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Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00256.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. L822-L828 ◽

Cited By ~ 17

Author(s):

R. Blair Dodson ◽

Matthew R. Morgan ◽

Csaba Galambos ◽

Kendall S. Hunter ◽

Steven H. Abman

Keyword(s):

Pulmonary Hypertension ◽

Main Pulmonary Artery ◽

Pulmonary Arteries ◽

Clinical Syndrome ◽

Late Gestation ◽

Biaxial Testing ◽

Mechanical Stiffness ◽

Sheep Model ◽

Fetal Sheep ◽

Ecm Remodeling

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness ( P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.

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