Therapies for Fetal Growth Restriction: Effects on the Health of Adult Offspring

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dc.contributor.advisor Stanley, J en Mills, Valerie en 2016-10-05T20:49:52Z en 2016 en
dc.identifier.uri en
dc.description Full text is available to authenticated members of The University of Auckland only. en
dc.description.abstract Fetal growth restriction (FGR) is a major pregnancy complication affecting up to 10% of pregnancies. FGR is associated with, not only significant perinatal mortality and morbidity, but also increased risk to hypertension, insulin resistance, obesity and cardiovascular disease in adulthood. Although the underlying cause of FGR is not well understood, placental insufficiency has been implicated as a major contributor to this pathology. At present there are no curative therapies available when FGR presents in the clinic. A therapy for FGR would, not only have significant benefits in improving perinatal mortality and morbidity outcomes of these pregnancies, but also have the potential to improve these metabolic and cardiovascular outcomes. Sildenafil citrate treatment is one such potential therapy for FGR, as enhanced placental perfusion would improve fetal substrate supply, potentially reversing the effects of placental insufficiency. In this study we utilised the eNOS-/- deficient mouse, a model of fetal growth restriction. Pregnant dams were randomised onto sildenafil treatment at gd 12.5 until birth at gd 19.5. After weaning offspring were fed either a high fat (HFD) or normal chow diet (ND), and raised until two time points; postnatal day 90 and 150. Glucose tolerance, systolic blood pressure, insulin concentration, vascular reactivity and various other measures were analysed in this study. We found that eNOS-/- offspring were significantly smaller than their C57BL/6J controls at weaning and P90; at P150 they had ‘caught up’ and were a similar weight. Total adipose tissue deposition at P90 was significantly increased in eNOS-/- HFD offspring compared to C57BL/6J mice (eNOS-/- vs C57BL/6J: 5.34 ± 0.59% vs 3.01 ± 0.56%, p=<0.001). There was a trend towards this increased adipose tissue deposition being attenuated by in utero exposure to sildenafil. At P150, however, both C57BL/6J and eNOS-/- offspring fed a high fat diet demonstrated significant adipose tissue deposition (C57BL/6J: ND- vs HFD- :2.22 ± 0.08% vs 5.02 ± 0.36%, p=<0.001) and (eNOS-/-: ND+ vs HFD+ :2.07 ± 0.15 vs 5.29 ± 0.72%, p=<0.001). These results may indicate an increased propensity for adipose tissue deposition and an advanced aging phenotype in eNOS-/- offspring. Both diet and maternal sildenafil treatment had a significant effect on glucose tolerance. There was a significant impairment in eNOS-/- mice fed a high fat diet – this was significant in offspring from vehicle treated mothers at P90, and in both vehicle and sildenafil exposed offspring at P150. Kidney weight at both P90 and P150 was significantly reduced in eNOS-/- offspring but this was not linked to blood pressure changes. At P90 there was a treatment effect in eNOS-/- offspring; arteries from those mice exposed to vehicle were more sensitive to vasoconstrictor U46619 than their sildenafil exposed counterparts. Both a high fat diet and sildenafil treatment was associated with increased endothelium-dependent relaxation in arteries from C57BL/6J mice. Sildenafil treatment had subtle effects on vascular function, including attenuation of an increased sensitivity to vasoconstriction in eNOS-/- offspring on a high fat diet. Again, dysregulation was observed in vehicle treated offspring which was not present for sildenafil treated eNOS-/- offspring. Together with the small but positive effects on metabolic indices, there is limited evidence that exposure to sildenafil treatment in utero may have subtle beneficial effects in adult offspring born growth restricted. There is clearly scope for these effects to be studied in other models, particularly if an increase in fetal growth can also be demonstrated. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof Masters Thesis - University of Auckland en
dc.relation.isreferencedby UoA99264888712502091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights Restricted Item. Available to authenticated members of The University of Auckland. en
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dc.rights.uri en
dc.title Therapies for Fetal Growth Restriction: Effects on the Health of Adult Offspring en
dc.type Thesis en Biomedical Science en The University of Auckland en Masters en
dc.rights.holder Copyright: The author en
pubs.elements-id 542266 en
pubs.record-created-at-source-date 2016-10-06 en

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