Obese women are at increased risk of developing a pregnancy specific hypertensive disorderpreeclampsia, associated with endothelial dysfunction. Oxidative stress and/or damage have beenobserved in both the placenta and vasculature of women with preeclampsia. Women with a history ofpreeclampsia have an increased risk of developing cardiovascular disease later in life. Women with preexistingobesity have numerous characteristics that we propose will contribute to feed-forward redoxcycling during pregnancy, increasing the burden of oxidative stress during pregnancy. The goal of thisproject is to identify redox-cycling mechanisms present early in pregnancy that can lead to oxidative stressand produce markers of oxidant damage that are associated with preeclampsia. These mechanismsinclude 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 froman antioxidant to a prooxidant that contributes to feed-forward oxidation in the circulation due to poorcopper binding. These early pregnancy oxidative challenges will surpass the antioxidant capacity of manyobese women. The pathways most likely impacted by redox cycling and declining antioxidant availabilityinclude immune cell function, placental antioxidant status, and compromised vascular adaptation topregnancy at the level of NO-bioavailability (in part due to sequestering of NO in free fatty acid modifiedalbumin, and consumption by extracellular matrix bound myeloperoxidase. Our project seeks to examineplausibility of these mechanisms to produce oxidative stress early in pregnancy, and in patients thatdevelop preeclampsia (Aim 1). The capacity of neutrophils and monocytes to contribute to theaccumulation of the vasoactive products, and the localization of MPO and its functional consequences onvascular function and oxidation will be examined in Aim 2. A rat model will be used to establish the impactof adiposity on inflammation/oxidation and the vascular adaptation to pregnancy. This model will also beused for in vivo studies to further elucidate the mechanisms of vascular dysfunction and potentialinterventions (Aim 3). This project seeks to identify specific pathways of oxidant stress associated withadiposity that may provide insight into potential therapeutic strategies to reduce detrimental oxidativedamage associated with preeclampsia, as well as reducing their risk of future cardiovascular disease.
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| Hux, Vanessa J; Roberts, James M; Okun, Michele L (2017) Allostatic load in early pregnancy is associated with poor sleep quality. Sleep Med 33:85-90 |
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| Hux, Vanessa J; Roberts, James M (2015) A potential role for allostatic load in preeclampsia. Matern Child Health J 19:591-7 |
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| Founds, Sandra A; Ren, Dianxu; Roberts, James M et al. (2015) Follistatin-like 3 across gestation in preeclampsia and uncomplicated pregnancies among lean and obese women. Reprod Sci 22:402-9 |
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