Alcohol and Maternal Uterine Vascular Adaptations in Pregnancy

妊娠期酒精与母体子宫血管适应

• 批准号: 9053392
• 负责人: Jayanth Ramadoss
• 金额: $ 32.74万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053392
• 关键词: Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Arteries; Attention; Behavioral; Birth Weight; Blood Circulation; Blood Vessels; Brain; Child; Chronic; Complex; Data; Development; Endothelium; Epoprostenol; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Growth; Functional disorder; Goals; Growth; Health; Histology; Human; Image Analysis; Immunoblotting; Impairment; Individual; Measures; Methods; Modeling; Myography; NOS3 gene; National Institute on Alcohol Abuse and Alcoholism; Neonatal; Neurodevelopmental Deficit; Nitric Oxide; Nitric Oxide Synthase; Outcome; Pathway interactions; Phosphorylation Site; Pregnancy; Prevalence; Prevention strategy; Production; Prostaglandins I; Rattus; Regulation; Relaxation; Research; Reverse Transcriptase Polymerase Chain Reaction; Saline; Schools; Spectrophotometry; Speed; Strategic Planning; System; Testing; Time; United States; Vascular Diseases; Vasodilation; Vasodilator Agents; alcohol effect; alcohol exposure; alcohol research; binge drinking; body system; cost; disability; effective intervention; feeding; fetal; fluorescence imaging; frontier; in vivo; in vivo Model; indexing; innovation; novel; nutrition; pregnant; prevent; programs; reproductive; research study

DESCRIPTION (provided by applicant): Alcohol & Maternal Uterine Vascular Adaptations in Pregnancy Maternal alcohol abuse during pregnancy can result in Fetal Alcohol Spectrum Disorders (FASD), a lifelong disability characterized by a range of growth and developmental deficits. Current estimates of FASD prevalence is about 2-5% among young school children in the United States. Efforts to successfully prevent or ameliorate the teratogenic effects of ethanol have been impeded, at least in part, by a limited understanding of alcohol's complex mechanisms of action involving multiple organ systems. A normal pregnancy is associated with major uterine circulatory adaptations that directly relates to fetal growth, neonatal birth weights and survival. A cardinal feature of fetal alcohol syndrome is growth restriction, but traditionally alcohol studies have focused on brain/behavioral deficits, and little attention has been paid to critical gestational uterine vascular adaptations. We herein show novel preliminary data that alcohol impairs the exquisite regulation of gestational uterine circulatory adaptations in rat bing alcohol model. We herein hypothesize that chronic binge alcohol exposure during pregnancy impairs maternal uterine artery vascular adaptations via endothelial nitric oxide (NO) system dysregulation. Aim#1 will test the hypothesis that binge alcohol exposure in pregnancy leads to impaired endothelium-dependent maternal uterine artery relaxation. Following binge paradigm, we will assess growth indices, and utilize wire myography to study agonist-induced uterine artery relaxation in endothelium-intact/denuded vessels from saline control, pair-fed nutrition control, and alcohol rats. Aim#2 will test if binge alcohol impairs uterine artery relaxation via endothelium-derived NO relative to prostacyclin/endothelium-derived hyperpolarizing factor, decreases uterine artery NO production, endothelial NO synthase (eNOS) expression, and impairs eNOS multi-site phosphorylation. Aim#3 will test if binge alcohol decreases uterine artery NO, decreases excitatory Pser1177eNOS levels, and increases inhibitory Pthr495eNOS levels via ERK/AMPK pathway, and alcohol effects on endothelial [Ca+2]i transients. In Aims#2 and #3, we will assess uterine artery relaxation after blocking major vasodilatory pathways and conduct mechanistic studies with/without eNOS activity/multi-site phosphorylation-regulating pathway antagonists via RT-PCR, immunoblotting, histology, fluorescent imaging and spectrophotometry. Simultaneous [Ca2+]i-NO fluorescent imaging will be performed utilizing high-speed excitation/emission wavelength switching system. Our proposal explores a new frontier of gestational alcohol research by developing the first mechanistic framework for binge alcohol-induced uterine artery adaptations and identifying alcohol targets in an in vivo model. In alignment with NIAAA FY14 Strategic Plan, our proposal utilizes powerful methods and presents a new maternal-inclusive paradigm to the FAS field and predicts that a more effective intervention will require innovative pharmacologic targeting of maternal systems, especially the critical uterine circulation, in order to predict and propose a therapy that will have a real promie as a preventive strategy.

描述（由申请人提供）：怀孕期间的酒精和母体子宫血管适应 母体在怀孕期间酗酒可导致胎儿酒精谱系障碍 (FASD)，这是一种以一系列生长和发育缺陷为特征的终身残疾。目前估计美国幼儿中 FASD 的患病率约为 2-5%。成功预防或改善乙醇致畸作用的努力 至少部分地，由于对酒精涉及多个器官系统的复杂作用机制的了解有限。正常妊娠与主要的子宫循环适应有关，而子宫循环适应与胎儿生长、新生儿出生体重直接相关 和生存。胎儿酒精综合症的一个主要特征是生长受限，但传统上 酒精研究主要集中在大脑/行为缺陷上，而很少关注关键的妊娠子宫血管适应。我们在此展示了新的初步数据，表明酒精会损害大鼠酒精模型中妊娠子宫循环适应的精细调节。我们在此假设，怀孕期间长期酗酒会通过内皮一氧化氮（NO）系统失调损害母体子宫动脉血管适应。目标#1 将检验以下假设：怀孕期间酗酒会导致内皮依赖性母体子宫动脉松弛受损。按照暴饮暴食模式，我们将评估生长指数，并利用肌线描记术来研究来自盐水对照、配对喂养营养对照和酒精大鼠的内皮完整/裸露血管中激动剂诱导的子宫动脉松弛。 Aim#2 将测试酗酒是否通过相对于前列环素/内皮源性超极化因子的内皮源性 NO 损害子宫动脉松弛，减少子宫动脉 NO 产生、内皮 NO 合酶 (eNOS) 表达，并损害 eNOS 多位点磷酸化。 Aim#3 将测试酗酒是否会通过 ERK/AMPK 途径降低子宫动脉 NO、降低兴奋性 Pser1177eNOS 水平并增加抑制性 Pthr495eNOS 水平，以及酒精对内皮 [Ca+2]i 瞬变的影响。在目标 #2 和 #3 中，我们将评估阻断主要血管舒张途径后的子宫动脉松弛情况，并通过 RT-PCR、免疫印迹、组织学、荧光成像和分光光度法进行有/无 eNOS 活性/多位点磷酸化调节途径拮抗剂的机制研究。将利用高速激发/发射波长切换系统同时进行 [Ca2+]i-NO 荧光成像。我们的提案通过开发第一个酗酒引起的子宫动脉适应机制框架并确定体内模型中的酒精目标，探索了妊娠酒精研究的新领域。根据 NIAAA 2014 财年战略计划，我们的提案利用强大的方法，向 FAS 领域提出了一种新的孕产妇包容范式，并预测更有效的干预措施将需要针对孕产妇系统，特别是关键的子宫循环进行创新的药理学靶向，以便预测并提出一种真正有希望作为预防策略的疗法。