Physiologic Cardiovascular & Uterine eNOS Responses:Role of Endogenous Estrogen

生理心血管

• 批准号: 7635379
• 负责人: RONALD R MAGNESS
• 金额: $ 16.8万
• 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/7635379
• 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

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 is 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) NOand 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.

雌激素和一氧化氮产生之间的相互作用是显著的，因为功能障碍是在