Physiologic Cardiovascular & Uterine eNOS Responses:Role of Endogenous Estrogen

生理心血管

• 批准号: 7663772
• 负责人: RONALD R MAGNESS
• 金额: $ 53.55万
• 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/7663772
• 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; Perfusion; Peripheral; 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; ilium; in vivo; inhibitor/antagonist; pregnant; 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（由申请人提供）：雌激素和NO产生之间的相互作用是显着的，因为在先兆子痫伴IUGR中注意到功能障碍。雌激素受体（ER）拮抗剂ICI 182，780和NOS抑制剂L-NAME显著抑制妊娠诱导的UBF升高（35-40%），表明内源性ER激活和DA内皮NO产生之间存在因果关系。我们将集中在妊娠晚期测试的总体假设，雌激素维持正常的心血管适应性，通过eNOS水平和NO生产的子宫动脉内皮细胞的水平。具体目标1：来曲唑阻断绵羊内源性雌激素作用动物模型的建立（CGS 20267）; IC 1182，78，L-NAME和DHEA效应：特定目的II：体内：生理心血管适应（外周、心脏和子宫）和激素来曲唑给药妊娠绵羊中的类固醇激素、cGMP和一氧化氮（NOx）变化：特定目的III：离体/体外：来自媒介物和来曲唑处理的妊娠绵羊的子宫动脉中的机制性细胞和分子信号传导变化：a）UA内皮产生基础和刺激（ATP和离子霉素）NO的能力以及初始和持续的[Ca 2 + ]\爆发在该响应中的作用。将评价雌激素受体、剪切应力以及ERK-1/2和PI 3激酶AKT信号通路的特定机制作用。由于UBF的调节对于向发育中的胎儿提供适当的营养和氧气是强制性的，因此这些血管舒张机制对胎儿的生长和发育具有显著影响。芳香化酶抑制剂来曲唑产生的数据将直接确定母体：胎儿界面产生的胎盘雌激素在调节子宫胎盘血流中的作用。