Chamley, LBarrett, CGuild, SChen, QLau, Sien2014-08-1220142014http://hdl.handle.net/2292/22724Introduction Preeclampsia is a disorder of human pregnancy characterised by new-onset hypertension and proteinuria. The clinical presentation of preeclampsia is heterogeneous and there is no definitive cure except the early delivery of the placenta. It is currently believed that the onset of preeclampsia is triggered by an unknown factor released from the placenta but the pathogenesis is dependent on the maternal response to this trigger, which is modifiable by underlying maternal risk factors. The largest maternal risk factor for preeclampsia is the presence of antiphospholipid antibodies. In normal pregnancy, the turn-over of the syncytiotrophoblast results in the release of up to 3g of ‘trophoblast debris’ into the maternal blood through a process akin to apoptosis. In preeclampsia, the release of trophoblast debris is thought to occur by necrosis. Previous work has demonstrated the presence necrotic trophoblast debris activates endothelial cells and injection of necrotic trophoblast debris into pregnant rats resulted in a relative increase in mean arterial blood pressure. The underlying molecular mechanisms by which these effects occur, and whether those effects change in the presence of a maternal risk factor, are unknown. The aim of this thesis is to understand how antiphospholipid antibodies may alter the maternal response to necrotic trophoblast debris, and whether this interaction produces the clinical signs of preeclampsia. Methods A systematic review and meta-analysis was performed to compare the circulating concentrations of tumour necrosis factor-alpha, interleukin-6, interleukin-10, soluble fms-like tyrosine kinase-1, soluble endoglin and soluble endothelin-1, in preeclamptic and normotensive pregnancies. A model of a maternal risk factor for preeclampsia was created in the pregnant rat using intravenous injections of murine monoclonal antiphospholipid antibodies. To create a model which encompasses both a placental trigger and a maternal risk factor for preeclampsia, pregnant rats were given intravenous injections of antiphospholipid antibodies and necrotic trophoblast debris. Isobaric tags for relative and absolute quantification mass spectrometry was used to investigate relative changes in the proteome of endothelial cells after exposure to apoptotic or necrotic trophoblast debris. Results The systematic review identified all six biomarkers as clinically relevant features to potentially examine in an animal model for preeclampsia. The model of a maternal risk factor for preeclampsia using antiphospholipid antibodies established circulating antiphospholipid antibodies concentrations deemed clinically relevant in humans, without significant fetal loss. Pregnant rats receiving antiphospholipid antibodies exhibited increased glomerular endotheliosis. In pregnant rats receiving both antiphospholipid antibodies and necrotic trophoblast debris, there was an alteration in the vasculature including smaller decreases in systolic arterial pressure and lower cardiac output, but increased peripheral vascular resistance accompanied by proteinuria. The exposure of endothelial cells to necrotic or apoptotic trophoblast debris resulted in only a few alterations to the proteome of the endothelial cells including increased expression of vitronectin which may play a role in the recognition and response to trophoblast debris. The expression of endoglin in endothelial cells was up-regulated in response to necrotic trophoblast debris. Conclusion While hypertension per se was not observed in the antiphospholipid antibodies and necrotic trophoblast debris model, increased proteinuria and alterations to the vasculature were observed in response to aPL and necrotic trophoblast debris and these are features of preeclampsia. The increased expression of endoglin by endothelial cells in response to necrotic trophoblast debris in vitro fits with the altered vascular response to antiphospholipid antibodies and necrotic trophoblast debris in vivo, and the reports of increased soluble endoglin in preeclampsia.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.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmThesisCopyright: The Authorhttp://purl.org/eprint/accessRights/OpenAccessQ111964007