Pre-eclampsia affects about 5% of all pregnant women and is one of the most important pregnancy complications world-wide. Life threatening complications require an immediate medical management of pre-eclampsia. However, as the origin of this disease is still unexplained, diagnosis, treatment and management still pose a challenge. The aim of this thesis was to investigate the involvement of small metabolites and oxylipins in pre-eclampsia and the regulation of the vascular tone. A metabolomics analysis of maternal blood plasma enabled identification of a range of biomarkers. These were putatively identified as 12,13-epoxy-9-oxoODE, methionine sulfoxide, guanidoacetic acid, uric acid, p-cresol sulfate, hydroxyhexacosanoic acid as well as the bile acid isomers taurodeoxycholic acid, tauroursodeoxycholic acid and taurochenodeoxycholic acid. A targeted LC-MS/MS method was used to determine oxylipin levels in maternal plasma, fetal plasma, chorionic plate arteries and stem villi from healthy and preeclamptic subjects. Significantly differing oxylipin levels were found in maternal plasma, fetal plasma and chorionic plate arteries. Arachidonic acid, 5,6-DHET, 8-HETE, 11-HETE, 15-HETE, 9-oxoODE, 13-oxoODE were decreased and 13-HODE was increased in maternal blood plasma in late onset pre-eclampsia. In early onset pre-eclampsia 5-HETE was significantly increased in maternal plasma. In cord blood plasma, 9-oxoODE, 13-oxoODE, 9-HODE and 13-HODE levels significantly increased in late onset pre-eclampsia. In chorionic plate arteries, arachidonic acid, 14,15-DHET, 5-HETE and 15-HETE were increased in late onset pre-eclampsia. Gene expression studies were conducted to determine levels of CYP2J2, EPHX1, EPHX2, PPARA and PPARG in chorionic plate arteries. All genes were detected on RNA level in this tissue region and were stably expressed across healthy and preeclamptic subjects. Vascular effects of CYP P450 derived oxylipins were assessed in chorionic plate arteries and stem villous arteries. No effects were observed for the four EET (epoxyeicosatrienoic acid) isomers , four DHET (dihydroxyeicosatrienoic acids) isomers or 5-, 15- and 20-HETE (hydroxyeicosatetraenoic acids), except for a weak dilating effect of 8,9-DHET on stem villous arteries. In addition to this, PPAR-alpha agonist Wy14643 and PPAR-gamma agonist ciglitazone were examined for effects in the placental vasculature. Potent dilating effects were demonstrated for both compounds in chorionic plate arteries and stem villous arteries. In conclusion, this thesis demonstrated that pre-eclampsia is characterised by complex changes in levels of small metabolites and oxylipins. The identified biomarkers provide new insights into ongoing pathophysiological processes in the pre-eclamptic syndrome. The physiological significance of changed oxylipin levels needs still to be determined. However, as oxylipins are known ligands of PPAR receptors, which were demonstrated to be expressed in the placenta, the PPAR signalling pathway is a promising target for future studies in pre-eclampsia.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:701223 |
| Date | January 2016 |
| Creators | Sander, Katrin Natsumi |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/36417/ |
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