Fetal growth restriction (FGR) signifies that the fetus has not achieved its growth potential and is associated with increased perinatal mortality and morbidity. The exact aetiology of FGR, in the absence of any identifiable fetal and maternal factors, remains unclear and is attributed to placental insufficiency. The FGR placenta has a characteristic phenotype including: increased resistance in the fetoplacental circulation, an alteration in trophoblast cell turnover and reduced activity of placental nutrient transport systems, the best characterised being the amino acid transporter, system A. The placenta strongly expresses the cortisol inactivating enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 11β-HSD2 activity was reduced in placentas from pregnancies complicated by FGR, suggesting increased exposure of the fetoplacental unit to maternal cortisol. In animal models, excessive exposure to glucocorticoids (GCs) is associated with a reduction in both fetal and placental weight. This reduction in placental weight was associated with abnormalities in placental function, consistent with those observed in the FGR placenta. This PhD investigated whether excess GC exposure during pregnancy is responsible placental insufficiency in human pregnancies and tested the hypotheses that excess GC exposure adversely affects placental vascular tone, trophoblast cell turnover and activity of the amino acid transporter, system A. Term placentas were collected from uncomplicated pregnancies and first trimester placental samples were obtained following elective surgical termination of pregnancy. Wire myography was used to explore the acute and chronic effects of GCs on term chorionic plate artery (CPA) function. The impact of GC treatment on trophoblast cell turnover in both first trimester and term placenta was investigated using the placental explant system. The effect of GCs on the activity of the system A transporter was also investigated in term explants and in isolated cytotrophoblasts where the expression of 11β-HSD2 was reduced using siRNA. Gene microarray studies on first trimester placental explants treated with GCs were utilised to identify genes regulated by GCs. Blunted constriction to thromboxane A2 was observed following acute GC treatment, whilst chronic exposure resulted in enhanced vasoconstriction, mimicking the altered reactivity of CPAs from pregnancies complicated by FGR. GC excess in first trimester placental explants increased apoptosis and decreased proliferation, thereby replicating the disordered turnover of the trophoblast observed in FGR placentas. No demonstrable effect was observed in cell turnover or system A activity in term placental explants treated with GCs, however, these experiments were hindered by the in-vitro regeneration of the syncytiotrophoblast in the model employed. The attenuation of 11β-HSD2 activity observed in FGR placentas was replicated in term primary cytotrophoblasts utilising siRNA to knock-down expression of 11β-HSD2. Preliminary results suggested an increase in system A activity in response to cortisol. Gene microarray studies identified a significant number of genes (~500) that were regulated by dexamethasone, confirming that GCs have an impact on many aspects of placental function. Potential mediators for the characteristic features of the FGR placenta replicated here in response to GC treatment were identified and validated at the mRNA level. The studies described in this thesis support the hypotheses that GC excess within the placenta contributes to the development of raised vascular resistance in the fetoplacental circulation and the disordered trophoblast turnover in placentas from pregnancies complicated by FGR. However, with the preliminary studies performed, the hypothesis that elevated levels of GCs contribute to the reduced placental amino acid transfer by the system A transporter in the FGR placenta can not be confidently disproven.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:553478 |
| Date | January 2012 |
| Creators | Nugent, Justine Lucy |
| Contributors | Jones, Rebecca; Sibley, Colin; Wareing, Mark |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/effects-of-glucocorticoids-on-placental-development-and-functionimplications-for-fetal-growth-restriction(b27d81f1-8d97-4be8-8fed-fa28743e42fa).html |
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