Oxidative Stress during Reduced Uterine Perfusion

描述（由申请人提供）： 妊娠特异性疾病先兆子痫发生在所有妊娠的3 - 10%中。这种高血压疾病仍然是发达国家孕产妇和围产期死亡率的主要原因之一，尽管在围产期和母胎医学方面取得了重大进展。虽然病因学和发病机制仍不清楚，但该疾病的某些方面已得到充分证实。这些包括动脉血管痉挛，外周血管阻力增加和器官灌注减少，这些都与血管内皮的整体功能障碍有关。氧化应激有助于疾病的病理生理学，因为抗氧化剂储备耗尽，活性氧产生增加。最近研究表明，抗氧化剂治疗（维生素C和E）可降低高危母亲患先兆子痫的风险。鉴于这些发现，了解胎盘灌注减少、氧化应激和血管行为改变之间的关系变得非常重要。Sprague-Dawley大鼠中的输尿管灌注减少（RIJPP）的手术模型改变母体生理学（即高血压、肾功能障碍）并产生KJGR。我们最近在实验室建立了这个模型，发现这些动物的动脉具有改变的内皮依赖性血管反应性。我们计划使用这个模型来研究假设：Jj。母体和胎盘的氧化应激导致RUPP的病理生理学。2)RUPP的抗氧化剂处理。动物将逆转与外科手术相关的一些（如果不是全部）有害变化。假设ii子宫灌注压（RUPP）的降低增加胎盘和子宫循环中的氧化应激。目标：通过测量脂质过氧化、组织氧化损伤和抗氧化剂利用率的组织水平，评估RUPP妊娠胎盘的氧化应激。目的Ib：通过测量血液和血管组织脂质过氧化水平、血管组织氧化损伤和循环抗氧化剂水平，评价RUPP大鼠母体循环中的氧化应激。目的Ic：研究RUPP诱导的胎盘和母体氧化应激是否可以用抗氧化剂治疗（维生素C）逆转。假设2：抗氧化剂治疗将改善RUPP诱导的母体生理和胎儿结局。目的2a：确定维生素C治疗后母体高血压是否得到改善。目标2b：确定RUPP大鼠维生素C治疗后母体血管反应性变化（肌源性反应性增加和内皮依赖性舒张降低）是否逆转。目的2c：确定维生素C治疗是否改善胎儿结局（胎儿体重、胎儿数量和胎儿死亡）。

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).