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Preeclampsia : pharmacologic studies in the trophoblast Pak Yee Rebecca Chow (24166164) PUREID: 437226797 Preeclampsia (PE) is a life-threatening complication of pregnancy that occurs four times more frequently in the presence of maternal diabetes. The anti- angiogenic factor soluble fms-like tyrosine kinase-1 (sFLT 1), released from the placenta, plays a crucial role in the development of PE. Currently, there is no specific treatment for PE. Delivery, often premature, is the only “cure”. It is therefore necessary to gain a better understanding of disease mechanisms and thus to identify potent drug targets in order to develop effective therapies. The aims of this project were (1) to identify potential signalling pathways that are regulated by sFLT1 and (2) to investigate whether these pathways play a role in an important complication of diabetic pregnancy, PE.<br><br>We established two in vitro models to study how stresses that are known to be amplified by diabetes, hypoxia and the presence of oxidized and glycated lipoproteins, modulate sFLT1 expression and release in human trophoblasts. We demonstrated that dimethyloxalylglycine (DMOG) could be used as a surrogate for “true” hypoxic conditions, and that a novel ‘Highly Oxidized Glycated (HOG-) LDL cell model’ can be used to investigate the effects of modified LDL on human trophoblasts. Then, we demonstrated that human trophoblasts express all three subtypes of a2-adrenergic receptors (a2-ARs). Functional studies suggested a limited role of a2-AR in the regulation of sFLT1 in trophoblasts. In studies of human placental tissues obtained at elective Caesarean Section, neither diabetes nor PE affected a2-AR expression. We then showed that PKC activation increased sFLT1 in human trophoblasts, and that PKC activity is increased in trophoblasts exposed to modified LDL, but not in placentas from women with diabetes, PE or both, although numbers available were very limited. The in vitro results are consistent with the possibility that modified LDL may promote PE development in women with diabetes, at least in part via PKC-mediated upregulation and release of sFLT 1. Diabetes may enhance PKC activity in the placenta before the clinical onset of PE, leading to increased sFLT1 production. The data provide new insights into disease mechanisms, and suggest potential targets for preventive and interventional measures for PE.<br> 2026-10-01T16:57:50Z Text Thesis 10.17034/32634144.v1 https://figshare.com/articles/thesis/Preeclampsia_pharmacologic_studies_in_the_trophoblast/32634144 All Rights Reserved