Actions of Estrogen on Uterine Artery Endothelium

雌激素对子宫动脉内皮的作用

基本信息

批准号：
7880711
负责人：
DONGBAO CHEN
金额：
$ 38.25万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-25 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880711
关键词：
Adult Affinity Anabolism Arteries Binding Biological Process Biology Blood Vessels Blood flow CAV1 gene Cardiovascular system Cell Culture Techniques Cell Nucleus Cell membrane Cell model Cells Cellular biology Complex Consensus Coupled DNA Methylation Data Disease Down-Regulation Embryo Endothelial Cells Endothelium Estradiol Estrogen Nuclear Receptor Estrogen Receptors Estrogen Replacement Therapy Estrogens Estrous Cycle Event Extracellular Signal Regulated Kinases Fetal Growth Retardation Fetus Figs - dietary GTP-Binding Proteins Gene Activation Gene Expression Genes Genetic Transcription Grant Human In Vitro JUN gene Ligands Luciferases Mediating Membrane Messenger RNA Minor Mitogen-Activated Protein Kinases Modeling Mothers Neonatal Nitric Oxide Nitric Oxide Synthase Nuclear Nuclear Envelope Pathway interactions Perinatal Personal Satisfaction Phosphorylation Play Pre-Eclampsia Pregnancy Production Prolactin Protein Isoforms Proteins Receptor Signaling Regulation Reporter Genes Research Research Personnel Research Support Response Elements Role Series Sheep Signal Pathway Signal Transduction Site Smooth Muscle Steroid Receptors Tissues Transcription Factor AP-1 Umbilical cord structure Vascular blood supply Veins activating transcription factor caveolin 1 design dimer driving force estradiol-bovine serum albumin fetal programming human NOS3 protein in utero in vivo inhibitor/antagonist innovation mortality neonatal morbidity non-genomic novel overexpression programs proliferative phase Menstrual cycle promoter protective effect protein activation protein expression receptor relating to nervous system response transcription factor

项目摘要

DESCRIPTION (provided by applicant): The hypothesis of this renewal grant is that, on binding to estrogen receptors (i.e., ERa and ER(3) on the plasma membranes, estrogen rapidly activates receptor subtype-specific intracellular signaling pathways (i.e., G-proteins) leading to endothelial nitric oxide (NO) synthase (eNOS) and extracellular signal-regulated kinases (ERK2/1) activation. Translocation of activated ERK2/1 stimulates the AP-1 (Jun/Fos dimers) transcription factors in the nucleus where they interact with ERa and ERp to reciprocally regulate eNOS and caveolin-1 expression by estrogen. Five specific aims will be studied by using the well-defined sheep uterine artery endothelial cell culture model and human umbilical cord vein endothelial cells. Aim 1: to determine the proximal membrane ER signaling events (G-protein activation) and if ERa and ERb play different roles in G-protein activation and eNOS-NO production and ERK2/1 pathway on estrogen stimulation. Aim 2: to determine if membrane and nuclear ERa and ERb are both involved in the reciprocal regulation of eNOS and caveolin-1 mRNA and protein expression by estrogen. Aim 3: to determine the role of c-Jun/Jun-B AP-1 in regulating eNOS and caveolin-1 expression by estrogen. Aim 4: to determine the transcriptional mechanism(s) underlying estrogen stimulation of endothelial eNOS expression, i.e., activation of eNOS promoter via ERa and ERb interaction with AP-1. Aim 5: to determine the mechanisms underlying down-regulation of endothelial caveolin-1 expression by estrogen, i.e., regulation of caveolin-1 promoter via ERa/ERb interaction with AP-1 and DNA methylation. These studies are of critical importance biologically because they are the first designed specifically for a comprehensive understanding of membrane ER initiated signaling cross-talk with classical nuclear ER via AP-1 to the regulation of eNOS and caveoln-1 gene activation in relation to endothelial NO production by estrogen unique to steroid receptor and endothelial biology. These studies are clinically important as dramatic estrogen biosynthesis and rise in uterine blood flow during pregnancy are essential for the bi-exchange between the mother and fetus and insufficient blood supply causes early embryonic loss, intrauterine growth restriction, preeclampsia, in utero fetal programming of adult diseases and reduced neonatal birthweight, which in turn inversely correlate to perinatal/neonatal morbidity/mortality and cardiovascular well-being of the mother. These studies are relevant to uncover the dilemma of the cardiovascular protective effects of estrogen.

描述（由申请人提供）：本次更新资助的假设是，在与质膜上的雌激素受体（即 ERa 和 ER(3)）结合后，雌激素迅速激活受体亚型特异性的细胞内信号通路（即 G-蛋白）导致内皮一氧化氮 (NO) 合酶 (eNOS) 和细胞外信号调节激酶 (ERK2/1) 激活易位。 ERK2/1 刺激细胞核中的 AP-1（Jun/Fos 二聚体）转录因子，在细胞核中它们与 ERa 和 ERp 相互作用，通过雌激素相互调节 eNOS 和 Caveolin-1 的表达。羊子宫动脉内皮细胞培养模型和人脐带静脉内皮细胞目的1：确定近端膜ER信号传导事件（G蛋白激活）和ERa。目标 2：确定膜和核 ERa 和 ERb 是否都参与 eNOS 和 Caveolin-1 mRNA 的相互调节。和雌激素的蛋白质表达。目标 3：确定 c-Jun/Jun-B AP-1 在雌激素调节 eNOS 和 Caveolin-1 表达中的作用。目标 4：确定雌激素刺激内皮 eNOS 表达的转录机制，即通过 ERa 和 ERb 与 AP-1 相互作用激活 eNOS 启动子。目标 5：确定雌激素下调内皮细胞 Caveolin-1 表达的机制，即通过 ERa/ERb 与 AP-1 和 DNA 甲基化相互作用来调节 Caveolin-1 启动子。这些研究在生物学上具有至关重要的意义，因为它们是第一个专门设计用于全面了解膜 ER 启动的信号传导与经典核 ER 通过 AP-1 的串扰，从而调节与内皮 NO 相关的 eNOS 和 Caveoln-1 基因激活由类固醇受体和内皮生物学特有的雌激素产生。这些研究具有重要的临床意义，因为怀孕期间雌激素生物合成的急剧增加和子宫血流量的增加对于母亲和胎儿之间的双向交换至关重要，并且血液供应不足会导致早期胚胎丢失、宫内生长受限、先兆子痫、成人子宫内胎儿编程疾病和新生儿出生体重减少，这反过来又与围产期/新生儿发病率/死亡率和母亲的心血管健康呈负相关。这些研究有助于揭示雌激素心血管保护作用的困境。