Oxidative Stress during Reduced Uterine Perfusion

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DESCRIPTION (provided by applicant): The pregnancy-specific disease preeclampsia occurs in 3 - 10 % of all pregnancies. This hypertensive disease remains one of the leading causes of maternal and perinatal mortality in developed countries despite major advances in perinatal and maternal-fetal medicine. While the etiology and pathogenesi<- remains unclear, certain facets of the disease are well established. These include arterial vasospasm, increased peripheral vascular resistance and decreased organ perfusion, which are all associated with a global dysfunction of the vascular endothelium. Oxidative stress contributes to the pathophysiology of the disease as antioxidant stores are depleted and reactive oxygen species production is increased. Recently it has been shown that antioxidant treatment (Vitamins C and E) decreases the risk of preeclampsia in high-risk mothers. Given these findings, it becomes important to understand the associations of reduced placental perfusion, oxidative stress and altered vascular behavior. A surgical model of reduced uierire perfusion (RIJPP) in Sprague-Dawley rats alters maternal physiology (i.e. hypertension, renal dysfunction) and produces KJGR. We have recently established this model in our laboratory, and have found that arteries from these animals possess altered endothelium-dependent vascular responsiveness. We plan to use this model to investigate the hypotheses that: Jj. maternal and placental oxidative stress contribute to the pathophysiology of RUPP. 2) that arti-oxidant treatment of RUPP. animals will reverse some if not all of the detrimental changes associated with the surgical procedure, Hypothesis ii Reductions in uterine perfusion pressure (RUPP) increase oxidative stress in both the placenta and the ma:ernal circulation. Aim la: To assess oxidative stress in the placentae of RUPP pregnancies by measuring tissue levels of lipid peroxidation, tissue oxidative damage and anti-oxidant availability. Aim Ib: To evaluate oxidative stress in the maternal circulation of RUPP rats by measuring blood and vascular tissue levels of lipid peroxidation, vascular tissue oxidative damage and circulating anti-oxidant levels. Aim Ic: To investigate whether RUPP-induced placental and maternal oxidative stress can be reversed with anti-oxidant treatment (Vitamin C). Hypothesis 2: Antioxidant treatment will improve the RUPP induced maternal physiology and fetal outcome. Aim 2a: To establish if maternal hypertension is ameliorated after Vitamin C treatment. Aim 2b: To determine if the maternal vascular reactivity changes (increased myogenic responsiveness and decreased endothelium-dependent relaxation) are reversed after Vitamin C treatment in RUPP rats. Aim 2c: To ascertain if Vitamin C treatment improves fetal outcomes (fetal weight, fetal number, and fetal demise).