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）：怀孕期间孕妇饮酒的酒精和子宫血管适应可能会导致胎儿酒精谱系（FASD），这是一种终身残疾，其特征是一系列生长和发育缺陷。在美国，当前对FASD患病率的估计约为2-5％。成功预防或改善乙醇的致畸作用的努力 至少部分地通过对酒精的复杂作用机理（涉及多个器官系统）的复杂机理的理解有限。正常妊娠与主要子宫循环适应有关，与胎儿生长，新生儿出生体重有关 和生存。胎儿酒精综合征的基本特征是生长限制，但传统上 酒精研究集中在大脑/行为缺陷上，对关键妊娠子宫血管适应的关注很少。我们在这里显示了新的初步数据，即酒精会损害大鼠Bing酒精模型中妊娠子宫循环适应的精致调节。我们在这里假设怀孕期间的慢性暴饮暴食暴露会通过内皮一氧化氮（NO）系统失调而损害母体子宫动脉血管适应。 AIM＃1将检验以下假设：妊娠中暴饮暴食会导致内皮依赖性母体子宫动脉松弛受损。在暴饮暴食范式之后，我们将评估生长指数，并利用金属丝图研究在盐水控制，配对营养控制和酒精大鼠的内皮INTACT/裸体血管中研究激动剂引起的子宫动脉松弛。 AIM＃2将测试是否通过内皮衍生的NO相对于前列环蛋白/衍生的内皮衍生的超极化因子损害了子宫动脉放松，减少子宫动脉否产生，内皮NO合酶（ENOS）表达，并损害Enos多点磷酸化。 AIM＃3将测试暴饮暴食是否降低子宫动脉NO，降低兴奋性PSER1177ENOS水平，并通过ERK/AMPK途径增加抑制性PTHR495ENOS水平，并对内皮[CA+2] I瞬态效应。在AIMS＃2和＃3中，我们将通过RT-PCR，免疫印迹，组织学，液体学成像和分类测定法进行了/不具有eNOS活性/多站点磷酸化调节途径的拮抗剂进行阻塞和进行机械研究后的子宫动脉松弛。同时[CA2+] I-NO荧光成像将使用高速激发/发射波长开关系统进行。我们的提案通过开发了狂饮酒精引起的子宫动脉适应的第一个机械框架并在体内模型中鉴定酒精靶标，从而探讨了妊娠酒精研究的新领域。为了与NIAAA FY14战略计划保持一致，我们的建议采用了强大的方法，并为FAS领域提供了新的包含母体的范式，并预测，更有效的干预措施将需要创新的药理学靶向产妇系统，尤其是关键的子宫循环，以预测和提出一种现实的策略，以预测和提出一种现实的策略。