Obstetrics and Gynaecology - Theses

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    Developing novel therapeutics for preeclampsia
    Brownfoot, Fiona ( 2016)
    Preeclampsia complicates 5-8% of pregnancies and is responsible for 60,000 maternal deaths and far greater numbers of perinatal deaths annually. Disappointingly these statistics have remained static over the last 50 years, owing to a lack of progress in developing clinical treatments. Excitingly, our field has made significant scientific advances in our understanding of the pathogenesis of preeclampsia in recent times. We now know that the preeclamptic placenta undergoes shallow invasion resulting in hypoxia, oxidative stress and inflammation that stimulate the release of two antiangiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG), into the maternal bloodstream. These factors inflict widespread endothelial damage, which culminate in the clinical features of preeclampsia, predominately high blood pressure and proteinuria. Importantly, the discovery of sFlt-1 and sENG as pathogenic proteins of preeclampsia has identified specific targets which treatments can be developed against. The goal of therapies may be to reduce endothelial dysfunction and stabilise the maternal disease process. This would reduce preeclampsia disease progression and may equate to gestation prolongation and improved perinatal and maternal outcomes. To address this goal, this thesis has one overarching aim; to identify novel small molecules that can reduce placental sFtl-1 and sENG secretion and mitigate endothelial dysfunction. In particular, we have focused on re-purposing medications from other fields, as they have known safety profiles, and examine their effect on these key features of preeclampsia using primary human tissues. We identified four medications; statins, YC-1, metformin and sulfasalazine, and examined their effect on these key pathophysiological features of preeclampsia. We showed that all of these medications reduced sFlt-1 secretion from primary human placenta by decreasing transcription and reducing expression of its placental splice variant, sFlt-1 e15a. YC-1, metformin and sulfasalazine all reduced sENG secretion, with the later two likely exerting an effect by reducing expression of its transmembrane bound cleavage protease MMP 14. In contrast, endothelial secretion of sENG was increased by statins. All of these medications improved various features of endothelial dysfunction, examined in a range of functional assays. In undertaking this research, we have also uncovered new layers of molecular regulation of sFlt-1 and sENG. We found that pravastatin was exerting an effect on sFlt-1 by blocking the cholesterol synthesis enzyme HMG CoA reductase. Metformin was reducing sFlt-1 and sENG secretion likely by inhibiting the mitochondrial electron transport chain. Whilst sulfasalazine is known to up-regulate the anti-oxidant enzyme heme-oxygenase 1 and inhibit NFκB, we demonstrated that it was not exerting its effect on sFlt-1 through these mechanisms. In conclusion, this work has identified four candidate small molecule treatments for preeclampsia and provided insights into the mechanisms regulating the placental secretion of anti-angiogenic factors. It has opened several new avenues for future research. Hopefully, this body of work will lead to the development and translation of the first medical treatment for preeclampsia and reduce the devastating morbidity and mortality experienced by mothers and their babies.