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Title: The nutrient exchange phenotype of the placenta in fetal growth restriction : characterization, adaptation and regulation
Author: Sibley, Colin
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2013
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An essential function of the placenta is the exchange of nutrients, and wasteproducts of fetal metabolism, between mother and fetus. The placenta thereforeplays a key role in determining fetal growth and size at birth. Fetal growthrestriction (FGR) is a complication affecting around 5% of pregnancies. Thereare several possible causes of FGR but the most common in the Western world isplacental dysfunction. The FGR baby is at much greater risk of stillbirth andneurodevelopmental morbidities than the normally grown baby. Furthermore, thesmaller baby per se has an increased risk of a range of morbidities as an adult.The thrust of the work covered in this thesis was to improve understanding of theabnormalities in placental exchange physiology associated with FGR. The goalwas (and is) to develop new placental diagnostic biomarkers for the disease andnew treatments based on improving placental function.The first tranche of work described showed that there are specific changes intransporter activities in the placenta in FGR. My colleagues and I showed thatSystem A amino acid transporter activity in the microvillous plasma membrane(MVM) of the syncytiotrophoblast (transporting epithelium of the placenta) isreduced, per mg membrane protein, and that this reduction is related to theseverity of the disease. This contrasted with our observation in normal pregnancythat MVM System A activity, per mg protein, is inversely related to size of the babyat birth, and first suggested the concept of placental adaptation to fetal growthdemand. We, and others, went on to show that a number of other transporters inthe syncytiotrophoblast are altered in FGR. However, not all transporters areaffected and at least one is upregulated. This led me to hypothesise that some ofthese changes are causal to FGR and some are responses, or adaptations, toabnormal fetal growth. The direct causes of transporter activity changes are notknown but our work, and that of others, suggests that glucocorticoids play a role.We also showed that transporter activities in the placenta are affected in othercomplications where fetal growth is aberrant. Furthermore, we provided evidencethat denuded areas of the syncytiotrophoblast might be the morphologicalcorrelate of a route of passive transfer of hydrophilic solutes across the placenta.Our studies in a mouse model of FGR suggest that abnormalities in such aparacellular route may be part of the placental dysfunction in the disease.In the final group of publications of this thesis I describe work showing gestationalchanges in placental transporter activities. I suggest that these are primarilyregulated to maintain fetal growth trajectory, but may also provide for specificnutrient demands at particular times in gestation. This explanation was supportedby work with genetically modified mice showing experimentally that placentaltransporter activity is regulated, or adapted, in relation to fetal growth demand. Itappears from several studies described here that there is a matching of fetalgrowth demand and placental nutrient supply. However, other work shows that thematernal nutritional environment does modify this matching.The studies described here have led to three ongoing lines of investigation: (1)applying knowledge of placental phenotypes of FGR to assist in early diagnosis ofwomen at risk; (2) using mouse models of FGR to test drugs for treating thedisease in humans; (3) investigations into the nature of the fetal nutrient demandsignal(s) to the placenta, and whether these signals are altered in FGR.
Supervisor: Aplin, John Sponsor: Not available
Qualification Name: Thesis (D.Sc.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Placenta ; Fetus