Obstetrics and Gynaecology - Theses
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ItemUnderstanding placental and cardiovascular adaptations in pregnancy: implications for therapeutic development for fetal growth restriction and preeclampsia.( 2021)Preeclampsia and fetal growth restriction are among the most serious obstetric conditions worldwide. Though they affect so many, we still do not completely understand their pathogenesis, nor have good ways to detect or treat them. In this thesis, I aimed to: improve our understanding of placental and vascular adaptations in preeclampsia and growth restriction, assess the ability of candidate therapeutics to mediate vascular dysfunction associated with preeclampsia, and to explore new models of preeclampsia and the long-term impacts on maternal cardiovascular health. DAAM2 and NR4A2 transcripts are elevated in the circulation of individuals whose pregnancies are complicated by fetal growth restriction (with or without preeclampsia). In Chapters 2 and 3 of this thesis, I identified these transcripts are expressed in the placenta, but their expression in either growth restricted or preeclamptic placenta does not mirror the increased expression of DAAM2 and NR4A2 in the maternal circulation. Thus, they are unlikely to originate from the dysfunctional placenta. However, their expression in the placenta throughout gestation, and clear regulation under hypoxia suggest they have roles in normal placental development and placental dysfunction. LOX-1 is elevated in the maternal vasculature in preeclampsia. In contrast to this, I identified in Chapter 4 that LOX-1 expression is reduced in the preeclamptic placenta. Furthermore, its expression is reduced in trophoblast under hypoxia. Treatment of trophoblasts with candidate preeclampsia therapeutics, esomeprazole and lansoprazole, (proton pump inhibitors) increased LOX-1 expression. These findings suggest that LOX-1 has a distinct role in the placenta compared to the vasculature. In Chapters 5 and 6, I assessed the ability of statins and new generation antiplatelets to mitigate preeclampsia-associated vascular dysfunction. In a model of endothelial dysfunction, pravastatin and simvastatin reduced secretion of vasoconstrictor, endothelin-1 and anti-angiogenic factor, sFLT-1. The new generation antiplatelet agents clopidogrel, prasugrel and ticagrelor reduced vasoconstriction of pregnant human omental (healthy and preeclamptic) and mouse mesenteric arteries through three different vasoconstrictors. Therefore, these candidate therapeutics can mitigate a key aspect of the pathogenesis driving preeclampsia. In Chapter 7, we established a model of preeclampsia in our laboratory through the blockade of nitric oxide synthesis (using L-NAME) to induce vasoconstriction. This led to elevated blood pressure, impaired fetal growth and elevated circulating levels of ‘toxic’ factors associated with preeclampsia. We were able to use this model to assess the effects of the new generation antiplatelet prasugrel, as a therapeutic, finding that prasugrel administration alongside L-NAME could reduce maternal blood pressure. I followed the dams post-delivery to investigate whether this model could simulate the long-term effects of preeclampsia on maternal cardiovascular health. I found that blood pressure and circulating toxic factors recovered as soon as 1 week post-delivery. At 10 weeks post-delivery, mice administered L-NAME during pregnancy demonstrated altered vascular reactivity, and increased expression of genes associated with inflammation in both the heart and kidney. However, these changes did not model the breadth of effects we anticipated, based on what is seen clinically post-preeclampsia. Overall, this thesis has added critical new knowledge regarding placental development, placental dysfunction, and vascular dysfunction. It provides further insight into the capability of novel candidate therapies for the prevention and treatment of preeclampsia, and provides new models of preeclampsia that can be used to enhance both our understanding of disease, and to assess future therapeutic potential.