Physiologic Cardiovascular & Uterine eNOS Responses:Role of Endogenous Estrogen

生理心血管

• 批准号: 7499532
• 负责人: RONALD R MAGNESS
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499532
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT Signaling Pathway; Address; Animal Model; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Arteries; Birth Weight; Blood; Blood flow; Cardiac; Cardiovascular system; Cyclic GMP; Cytochrome P450; Data; Development; Disease; Dose; Endothelial Cells; Endothelium; Enzymes; Estrogen Receptors; Estrogens; Fetal Growth; Fetal Growth Retardation; Fetus; Functional disorder; Growth and Development function; Hormonal; Hormonal Change; ICI 182780; In Vitro; Letrozole; Lonomycin; Maintenance; Maternal-Fetal Exchange; Mediating; Molecular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nutrient; Ovarian; Oxygen; Patient currently pregnant; Perfusion; Peripheral; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Physiological; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Tests; Production; Protein Isoforms; Receptor Activation; Regulation; Research Personnel; Role; Sheep; Signal Transduction; Steroids; Third Pregnancy Trimester; Time; Validation; Vasodilator Agents; dehydroepiandrosterone; fetal; ilium; in vivo; inhibitor/antagonist; programs; proliferative phase Menstrual cycle; reproductive; response; shear stress; steroid hormone; vascular bed

DESCRIPTION (provided by applicant): Interactions between estrogen and NO production are significant since dysfunctions are noted in preeclampsia with IUGR. Pregnancy-induced rises in UBF were significantly inhibited (35-40%) by Estrogen Receptor (ER) antagonist, ICI 182,780 and NOS inhibitor L-NAME suggesting cause and effect relationships exists between endogenous ER activation and DA endothelial NO production. We will focus on third trimester pregnancies testing the overall hypothesis that estrogen maintains normal CV adaptations via both eNOS levels and NO production at the level of the Uterine Artery endothelium. Specific Aim 1: Development of an Ovine Animal Model of Endogenous Estrogen Blockade Using Letrozole (CGS 20267); IC1182,78, L-NAME and DHEA effects: Specific Aim II: ln Vivo: Physiological cardiovascular adaptation (Peripheral, Cardiac and Uterine) and Hormonal (steroid hormones, cGMP and Nitric Oxide Metabolites (NOx) Changes in Letrozole-treated Pregnant Sheep: Specific Aim III: Ex Vivo/In Vitro: Mechanistic Cellular and Molecular Signaling Changes in Uterine Arteries from Vehicle and Letrozole-treated Pregnant Sheep: a) Ability of the UA endothelium to produce basal and stimulated (ATP and lonomycin) NO and the role of initial and sustained [Ca2+ ]\ bursts in this response. Specific mechanistic roles of estrogen receptors, shear stress, and the ERK-1/2 and PI3 Kinase AKT signaling pathways will be evaluated. Because regulation of UBF is mandatory for providing proper delivery of nutrients and oxygen to the developing fetus these vasodilator mechanisms have significant impacts on fetal growth and development. Data generated with the aromatase inhibitor Letrozole will directly define the role of placental estrogen produced at the maternal: fetal interface in regulating uteroplacental blood flows.

描述(申请人提供)：雌激素和一氧化氮的相互作用是显著的，因为在伴有IUGR的先兆子痫患者中注意到了功能障碍。雌激素受体(ER)拮抗剂ICI182,780和一氧化氮合酶抑制剂L-NAME显著抑制妊娠引起的UBF升高(35-40%)，提示内源性ER激活和DA内皮细胞NO产生之间存在因果关系。我们将重点研究妊娠晚期，测试雌激素通过eNOS水平和子宫动脉内皮细胞水平的NO产生来维持正常心血管适应的总体假设。特定目的1：用来曲唑(CGS 20267)建立内源性雌激素阻断的绵羊动物模型；IC1182，78，L-NAME和脱氢表雄酮的作用：特定目的II：LN在体：生理性心血管适应(外周、心脏和子宫)和激素(类固醇激素，cGMP和一氧化氮代谢产物(NOx)的变化来曲唑处理的怀孕绵羊：特定目的III：体外/活体：赋形剂和来曲唑处理的怀孕绵羊子宫动脉细胞和分子信号的机械变化：A)UA内皮产生基础和刺激(三磷酸腺苷和洛诺霉素)NO的能力以及初始和持续的[钙]暴发在这一反应中的作用。我们将评估雌激素受体、剪切力以及ERK-1/2和PI3Kinase AKT信号通路的具体机制作用。由于UBF的调节是为发育中的胎儿提供适当的营养和氧气所必需的，这些血管扩张机制对胎儿的生长和发育有重大影响。芳香酶抑制剂来曲唑产生的数据将直接确定母胎界面产生的胎盘雌激素在调节子宫胎盘血流中的作用。