MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
基本信息
- 批准号:6126001
- 负责人:
- 金额:$ 38.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-08-01 至 2004-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Although the uterine vascular effects of estrogen have been studied for over 70 years, the mechanism by which estrogen produces vasodilation remains unclear. Our laboratory was the first to show that a significant component of the uterine response to estrogen in the nonpregnant sheep is mediated by the release of nitric oxide (NO). We and others have shown that estradiol-17beta increases the expression and activity of endothelial nitric oxide synthase (eNOS) in the uterine circulation. However, it is not currently clear how this occurs or if, in addition to eNOS, neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) are also important in maintaining the sustained vasodilatory response seen after estrogen administration. Furthermore, it is not clear how estrogen modulates these NOS isoforms at the cellular and molecular level. Recently a new estrogen receptor, ERbeta has been isolated and emerging data suggest that this receptor may mediate a significant portion of the effects of estrogen in the vasculature. We hypothesize that uterine vasodilation produced by estradiol-17beta is mediated by specific interaction with both ERalpha and ERbeta, which subsequently activates eNOS (and potentially nNOS) via a nongenomic pathway, and iNOS via a genomic pathway, leading to increases in NO. The present application plans to evaluate the role of ER as a modulator of the NOS isoforms in the uterine circulation using a combination of physiologic and molecular endpoints. We will monitor the uterine hemodynamic responses to locally and systemically administered pharmacological antagonists that are selective for specific isoforms of NOS using a well-characterized ovine model. We intend to evaluate the expression of ERalpha and ERbeta in the ovine uterine vasculature and explore how estrogen alters eNOS, nNOS and NOS expression in endothelial cells and vascular smooth muscle. Finally we plan to determine if endogenous estrogen, acting through the uterine vascular NOS system, plays a critical role in increasing and maintaining uterine blood flow in late pregnancy. We believe that the information obtained in this revised application will provide new and important understanding into the mechanisms regulating vascular tone and hemodynamics in the uterine circulation in both the nonpregnant and pregnant animal.
虽然雌激素对子宫血管的影响已经研究了70多年,但雌激素产生血管舒张的机制仍不清楚。 我们的实验室是第一个表明,一个显着的组成部分,子宫对雌激素的非妊娠绵羊介导的释放一氧化氮(NO)。 我们和其他人已经表明,雌二醇-17 β增加子宫循环中内皮型一氧化氮合酶(eNOS)的表达和活性。 然而,目前尚不清楚这是如何发生的,或者除了eNOS之外,神经元型一氧化氮合酶(nNOS)或诱导型一氧化氮合酶(iNOS)是否在维持雌激素给药后观察到的持续血管舒张反应中也很重要。 此外,目前还不清楚雌激素如何在细胞和分子水平上调节这些NOS亚型。 最近,一种新的雌激素受体,ER β已被分离和新兴的数据表明,这种受体可能介导的雌激素在血管系统中的作用的显着部分。 我们假设雌二醇-17 β产生的子宫血管舒张是通过与ER α和ER β的特异性相互作用介导的,后者随后激活eNOS(和潜在的nNOS)通过非基因组途径,和iNOS通过基因组途径,本申请计划使用生理学和免疫组织化学的组合来评估ER作为子宫循环中NOS同种型的调节剂的作用。分子终点 我们将监测子宫的血流动力学反应,局部和全身给予药理学拮抗剂,选择性的特定亚型的NOS使用一个良好的羊模型。我们打算评估ER α和ER β在绵羊子宫血管中的表达,并探讨雌激素如何改变内皮细胞和血管平滑肌中eNOS、nNOS和NOS的表达。 最后,我们计划确定内源性雌激素是否通过子宫血管NOS系统发挥作用,在增加和维持妊娠晚期子宫血流方面发挥关键作用。 我们认为,在本修订申请中获得的信息将为非妊娠和妊娠动物子宫循环中血管张力和血流动力学的调节机制提供新的重要理解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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KENNETH E CLARK其他文献
KENNETH E CLARK的其他文献
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{{ truncateString('KENNETH E CLARK', 18)}}的其他基金
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6527425 - 财政年份:2000
- 资助金额:
$ 38.81万 - 项目类别:
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6390329 - 财政年份:2000
- 资助金额:
$ 38.81万 - 项目类别:
MOLECULAR MECHANISMS OF ESTROGENS VASCULAR ACTIONS
雌激素血管作用的分子机制
- 批准号:
6603399 - 财政年份:2000
- 资助金额:
$ 38.81万 - 项目类别:
ESTROGEN MODULATION OF THE CARDIOVASCULAR SYSTEM
雌激素对心血管系统的调节
- 批准号:
2227229 - 财政年份:1993
- 资助金额:
$ 38.81万 - 项目类别:
ESTROGEN MODULATION OF THE CARDIOVASCULAR SYSTEM
雌激素对心血管系统的调节
- 批准号:
2227230 - 财政年份:1993
- 资助金额:
$ 38.81万 - 项目类别:
EDRF REGULATION OF UTERINE AND UMBILICAL BLOOD FLOW
EDRF 对子宫和脐血流量的调节
- 批准号:
2225939 - 财政年份:1993
- 资助金额:
$ 38.81万 - 项目类别:
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