Oxidative Stress during Reduced Uterine Perfusion

描述(由申请人提供)：妊娠特有的疾病先兆子痫发生在所有怀孕的3%-10%。尽管围产期和母婴医学取得了重大进展，但这种高血压病仍然是发达国家孕产妇和围产期死亡的主要原因之一。虽然病因和发病机制尚不清楚，但该病的某些方面已经得到了很好的证实。这些包括动脉血管痉挛、外周血管阻力增加和器官灌注量减少，这些都与血管内皮细胞的整体功能障碍有关。氧化应激有助于疾病的病理生理，因为抗氧化剂的储存被耗尽，活性氧物种的产生增加。最近有研究表明，抗氧化治疗(维生素C和维生素E)可以降低高危母亲患先兆子痫的风险。鉴于这些发现，了解胎盘灌注量减少、氧化应激和血管行为改变之间的关系变得重要。一种减少输卵管血流灌注(RIJPP)的SD大鼠手术模型改变了母体生理(如高血压、肾功能障碍)，并产生IUGR。我们最近在我们的实验室建立了这个模型，并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以下假设：1)母体和胎盘氧化应激参与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部分(如果不是全部)有害变化，假设1：子宫灌注压(RUPP)的降低增加了胎盘和母体循环中的氧化应激。目的1a：通过检测胎盘组织中脂质过氧化水平、组织氧化损伤和抗氧化剂的有效性，评估RUPP妊娠胎盘的氧化应激状态。目的1b：通过检测血液和血管组织中脂质过氧化水平、血管组织氧化损伤和循环抗氧化水平，评价RUPP大鼠母体循环中的氧化应激状态。目的1c：探讨抗氧化剂(维生素C)能否逆转RUPP引起的胎盘和母体氧化应激。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：探讨维生素C治疗后孕妇高血压是否得到改善。目的2b：探讨维生素C对RUPP大鼠血管反应性改变(肌源性反应性增加和内皮依赖性松弛降低)是否有逆转作用。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 1 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 pathogenesis 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 IUGR. 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: 1) 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 1: Reductions in uterine perfusion pressure (RUPP) increase oxidative stress in both the placenta and the maternal circulation. Aim 1a: 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 1b: 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 1c: 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).