Obese women are at increased risk of developing a pregnancy specific hypertensive disorder preeclampsia, associated with endothelial dysfunction. Oxidative stress and/or damage have been observed in both the placenta and vasculature of women with preeclampsia. Women with a history of preeclampsia have an increased risk of developing cardiovascular disease later in life. Women with preexisting obesity have numerous characteristics that we propose will contribute to feed-forward redox cycling during pregnancy, increasing the burden of oxidative stress during pregnancy. The goal of this project is to identify redox-cycling mechanisms present early in pregnancy that can lead to oxidative stress and produce markers of oxidant damage that are associated with preeclampsia. These mechanisms include 1) activation of inflammatory cells and activation and release of myeloperoxidase (MPO), and 2) increased levels of circulating free fatty acids which bind to and modify albumin, converting albumin from an antioxidant to a prooxidant that contributes to feed-forward oxidation in the circulation due to poor copper binding. These early pregnancy oxidative challenges will surpass the antioxidant capacity of many obese women. The pathways most likely impacted by redox cycling and declining antioxidant availability include immune cell function, placental antioxidant status, and compromised vascular adaptation to pregnancy at the level of NO-bioavailability (in part due to sequestering of NO in free fatty acid modified albumin, and consumption by extracellular matrix bound myeloperoxidase. Our project seeks to examine plausibility of these mechanisms to produce oxidative stress early in pregnancy, and in patients that develop preeclampsia (Aim 1). The capacity of neutrophils and monocytes to contribute to the accumulation of the vasoactive products, and the localization of MPO and its functional consequences on vascular function and oxidation will be examined in Aim 2. A rat model will be used to establish the impact of adiposity on inflammation/oxidation and the vascular adaptation to pregnancy. This model will also be used for in vivo studies to further elucidate the mechanisms of vascular dysfunction and potential interventions (Aim 3). This project seeks to identify specific pathways of oxidant stress associated with adiposity that may provide insight into potential therapeutic strategies to reduce detrimental oxidative damage associated with preeclampsia, as well as reducing their risk of future cardiovascular disease.
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