VASCULAR REACTIVITY--GENDER AND HORMONAL INFLUENCES

血管反应性——性别和荷尔蒙的影响

• 批准号: 2692676
• 负责人: SUE P DUCKLES
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2692676
• 关键词: cerebrovascular system; estrogen receptors; estrogens; gender difference; gene targeting; genetically modified animals; hemodynamics; hormone receptor; hormone regulation /control mechanism; laboratory mouse; laboratory rat; melatonin; neuroprotectants; nitric oxide synthase; polymerase chain reaction; sex cycle; sex hormones; vasomotion; western blottings

DESCRIPTION: (Adapted from the application) Actions of estrogen on function of endothelial NOS may account for cerebrovascular protection. Thus, the first hypothesis is: 1) cerebrovascular responses involving NOS are affected by estrogen. Rat middle cerebral arteries in vitro will be used to test the influence of sex and gonadal steroids, comparing males and cycling females, control or gonadectomized and steroid-replaced. The investigator will compare myogenic tone in arteries from males and females and test whether NOS inhibition abolishes gender or estrous cycle differences. Possible K+ channel involvement will be investigated. Since shear stress stimulates the activity of NOS, the PI will test whether flow induced vasodilation is influenced by estrogen status and investigate modulation by gender and gonadal steroids. As a control, effects of gender and gonadal steroids on vasodilator responses to increased extracellular K+, which does not involve NOS will be investigated. The second hypothesis is: 2) estrogen acts by regulating levels of eNOS protein. Responses to endothelial dependent vasodilators, levels of NOS protein by Western blot and NOS activity will be measured, and NOSIII-deficient mice will be studied. For the third specific aim, the PI will test whether: 3) estrogen modulates effects of melatonin by a selective action on MT2 receptor mediated vasodilation. Circadian variation in cardiovascular disease onset has been shown and estrogen regulates vascular sensitivity to melatonin. The PI will determine whether melatonin causes constriction of cerebral arteries through MT1 and dilation via MT2 receptors. Influence of sex, transmural pressure, artery size and endothelial factors will be investigated. The PI will also test whether dilator responses via MT2 receptors are preferentially enhanced by estrogen exposure and using RT-PCR whether gonadal hormones alter expression of melatonin receptor subtypes. The final hypothesis is: 4) effects of estrogen are mediated by the classical estrogen receptor Estrogen receptor antagonists and estrogen receptor knockout mice will be used to test whether this receptor accounts for effects on cerebrovascular reactivity. Given the enormous impact of hormone replacement therapy, knowledge of the effects of gonadal steroids and melatonin on the cerebral circulation is essential.

描述：（改编自应用程序）雌激素对功能的作用 内皮细胞NOS的表达可能是脑血管保护作用的机制之一。 因此 第一个假设是：1）涉及NOS的脑血管反应是 受到雌激素的影响 体外大鼠大脑中动脉将用于 测试性别和性腺类固醇的影响，比较男性和骑自行车 雌性，对照或性腺切除和类固醇替代。 研究者 将比较男性和女性动脉中的肌源性张力， NOS抑制是否消除了性别或发情周期差异。 将研究可能的K+通道参与。 由于剪应力 刺激NOS的活性，PI将测试是否诱导流动 血管舒张受雌激素状态的影响，并研究 性别和性腺类固醇 作为对照，性别和性腺的影响 类固醇对血管舒张反应增加细胞外钾+，这并不 不涉及NOS将被调查。 第二个假设是：（2） 雌激素通过调节eNOS蛋白水平起作用。 Responses to 内皮依赖性血管扩张剂，NOS蛋白水平，Western blot 将测量NOS活性，并将NOSIII缺陷小鼠 研究了 对于第三个具体目标，PI将测试是否：3）雌激素 通过对MT 2受体的选择性作用调节褪黑激素的作用 介导的血管舒张。 心血管疾病发病的昼夜节律变化 雌激素调节血管对褪黑激素的敏感性 PI将确定褪黑激素是否会导致大脑收缩， 动脉通过MT 1和扩张通过MT 2受体。 性的影响， 跨壁压、动脉大小和内皮因子将被 研究了 PI还将通过MT 2测试扩张器是否有反应 受体优先增强雌激素暴露和使用RT-PCR 性腺激素是否改变褪黑素受体亚型的表达。 最后一个假设是：4）雌激素的作用是由 经典雌激素受体雌激素受体拮抗剂和雌激素 受体敲除小鼠将用于测试这种受体是否占 对脑血管反应性的影响 考虑到 激素替代疗法，了解性腺类固醇的作用 而褪黑激素对脑循环是必不可少的。