The expression of ovine placental lactogen, StAR and progesterone-associated steroidogenic enzymes in placentae of overnourished growing adolescent ewes

Lea, Richard G.; Wooding, Peter; Stewart, I. J.; Hannah, L T; Morton, Stephen W.; Wallace, Karen; Aitken, Raymond; Milne, John; Regnault, Timothy R. H.; Anthony, Russell V.; Wallace, Jean E.

doi:10.1530/rep-06-0294

Cited by 38 publications

(29 citation statements)

References 44 publications

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“…Clearly, both cardiac output and the partitioning of blood to the maternal versus gravid uterine tissues may be influenced by the increasing adiposity of the dams, but this aspect has not yet been directly measured in the overnourished paradigm. Irrespective of the putative mechanism, the early perturbation in fetal rather than maternal placental vascular development in overnourished pregnancies is in line with previous observations of a relative delay in ovine placental lactogen secretion in this model (indicative of inadequate binucleate cell migration from the fetal trophectoderm; Lea et al 2007) and with reduced proliferative activity within the fetal trophectoderm at the apex of placental growth (Lea et al 2005).…”

Section: Discussionsupporting

confidence: 89%

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

Redmer¹,

Luther²,

Milne³

et al. 2009

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To establish the basis for altered placental development and function previously observed at late gestation, fetoplacental growth and placental vascular development were measured at three stages of gestation in a nutritional paradigm of compromised pregnancy. Singleton pregnancies to a single sire were established and thereafter adolescent ewes were offered an optimal control (C) or a high (H) dietary intake. At day 50, the H group had elevated maternal insulin and amniotic glucose, whereas mass of the fetus and placenta were unaltered. At day 90, the H group exhibited elevated maternal insulin, IGF1 and glucose; fetal weight and glucose concentrations in H were increased relative to C, but placental weight was independent of nutrition. By day 130, total placentome weight in the H group was reduced by 46% and was associated with lower fetal glucose and a 20% reduction in fetal weight. As pregnancy progressed from day 50 to 130, the parameters of vascular development in the maternal and fetal components of the placenta increased. In the fetal cotyledon, high dietary intakes were associated with impaired vascular development at day 50 and an increase in capillary number at day 90. At day 130, all vascular indices were independent of nutrition. Thus, high dietary intakes to promote rapid maternal growth influence capillary development in the fetal portion of the placenta during early to mid-pregnancy and may underlie the subsequent reduction in placental mass and hence fetal nutrient supply observed during the final third of gestation.

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Section: Discussionsupporting

confidence: 89%

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

Redmer¹,

Luther²,

Milne³

et al. 2009

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“…As expected, oPL concentrations correlated with fetal weight; maternal oPL is produced in placental binucleate cells and is known to be positively correlated to placental weight and to fetal body weight (14,16). Placental lactogen concentration is reduced with fetal death in utero (30); although the frequency of sampling in this study was not sufficient to observe a decrease in oPL at fetal death, there was no significant association with cortisol, suggesting that there was no major placental pathology in these pregnancies.…”

Section: Discussionsupporting

confidence: 60%

“…In humans, stillbirth is frequently associated with maternal hypertension or diabetes (3,6,21,32) but is also increased in women with Cushing's disease (17,26,34,35) and maternal stress or depression (8,10,16,37), in which maternal cortisol would be chronically increased. Our study suggests that the adverse outcomes in ovine pregnancy with hypercortisolemia may be related to the metabolic effects of cortisol in the mother and/or fetus.…”

Section: Perspectives and Significancementioning

confidence: 99%

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

Keller‐Wood

Feng

Wood

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Keller-Wood M, Feng X, Wood CE, Richards E, Anthony RV, Dahl GE, Tao S. Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy. Am J Physiol Regul Integr Comp Physiol 307: R405-R413, 2014. First published June 11, 2014 doi:10.1152/ajpregu.00530.2013.-In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were designed to test the hypothesis that increased maternal cortisol would increase maternal glucose concentrations, suppress fetal growth, and impair neonatal glucose homeostasis. Ewes were infused with cortisol (1 mg·kg Ϫ1 ·day Ϫ1 ) from day 115 of gestation to term; maternal glucose, insulin, ovine placental lactogen, estrone, progesterone, nonesterified free fatty acids (NEFA), ␤-hydroxybutyrate (BHB), and electrolytes were measured. Infusion of cortisol increased maternal glucose concentration and slowed the glucose disappearance after injection of glucose; maternal infusion of cortisol also increased the incidence of fetal death at or near parturition. The design of the study was altered to terminate the study prior to delivery, and post hoc analysis of the data was performed to test the hypothesis that maternal metabolic factors predict the fetal outcome. In cortisol-infused ewes that had stillborn lambs, plasma insulin was increased relative to control ewes or cortisol-infused ewes with live lambs. Maternal cortisol infusion did not alter maternal food intake or plasma NEFA, BHB, estrone, progesterone or placental lactogen concentrations, and it did not alter fetal body weight, ponderal index, or fetal organ weights. Our study suggests that the adverse effect of elevated maternal cortisol on pregnancy outcome may be related to the effects of cortisol on maternal glucose homeostasis, and that chronic maternal stress or adrenal hypersecretion of cortisol may create fetal pathophysiology paralleling some aspects of maternal gestational diabetes. glucose; insulin; cortisol; pregnancy MATERNAL CORTISOL IS INCREASED in normal human pregnancy and is thought to contribute to the increase in maternal glucose concentration, as well as supporting increases in maternal plasma volume and cardiac output. In studies done in our laboratory, we have found that increasing maternal cortisol beyond the normal doubling in ovine pregnancy led to increased uterine blood flow and maternal and fetal glucose and lactate concentrations, whereas decreasing maternal cortisol to concentrations similar to those of nonpregnant ewes resulted in reduced uterine blood flow as gestation advanced (12, 13). Either increased or decreased maternal cortisol concentrations slowed the rate of fetal growth between 115 and 130 days of gestation. In women with Cushing's disease or Cushing's syndrome in pregnancy, there is also an increased incidence of small-for-gestational-age babies, as well as an increased risk of adverse pregnancy outcomes (26, 34). Maternal glucocorticoid treatme...

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“…Overnourishing the young adolescent, who is still growing during pregnancy, results in accelerated maternal tissue deposition with nutrient partitioning away from the gravid uterus at the expense of the fetus. FGR is accompanied by impaired placental vascularization and secretory function and reduced placental expression of VEGF and fms-related tyrosine kinase 1 (FLT1) (Redmer et al, 2005(Redmer et al, , 2009Lea et al, 2007). In common with human FGR, asymmetrical growth restriction with preservation of brain growth (brain sparing) and increased umbilical artery (UA) Doppler indices are apparent (Wallace et al, 2000;Carr et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

Carr

Wallace²,

Aitken³

et al. 2014

Human Gene Therapy

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Fetal growth restriction (FGR) occurs in ∼8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (n=45) or control intake (n=12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5×10¹¹ particles Ad.VEGF-A165 (n=18), control vector Ad.LacZ (n=14), or control saline (n=13). Fetal growth/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3-4 weeks postinjection (p=0.016-0.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight >2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and FLT1/KDR mRNA expression were increased in the maternal but not fetal placental compartments, suggesting downstream effects on placental function. Ad.VEGF gene therapy improves fetal growth in a sheep model of FGR, although the precise mechanism of action remains unclear.

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The expression of ovine placental lactogen, StAR and progesterone-associated steroidogenic enzymes in placentae of overnourished growing adolescent ewes

Cited by 38 publications

References 44 publications

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

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