VASCULAR REACTIVITY--GENDER AND HORMONAL INFLUENCES

描述：(改编自应用)雌激素对功能的作用 内皮型一氧化氮合酶的表达可能与脑血管保护有关。因此， 第一个假设是：1)涉及一氧化氮合酶的脑血管反应 受雌激素影响。体外培养的大鼠大脑中动脉将用于 测试性激素和性腺类固醇的影响，比较男性和骑自行车 女性，对照组或性腺摘除和类固醇替代。调查员 将比较男性和女性动脉的肌张力，并测试 抑制一氧化氮合酶是否会消除性别或发情周期的差异。 可能的K通道参与将被调查。自剪应力 刺激一氧化氮合酶的活性，PI将测试是否诱导流 血管扩张受雌激素状态的影响，并通过 性别和性腺类固醇。作为对照，性别和性腺的影响 类固醇对血管扩张剂对细胞外钾增加的反应，这确实 不涉及NOS的将被调查。第二个假设是：2) 雌激素通过调节eNOS蛋白水平发挥作用。对以下问题的回应 内皮依赖性血管扩张剂、一氧化氮合酶蛋白水平的Western印迹分析 并将测量一氧化氮合酶活性，NOSIII缺陷小鼠 学习。对于第三个特定的目标，PI将测试是否：3)雌激素 褪黑素对MT2受体的选择性调节作用 介导的血管扩张。心血管疾病发病的昼夜节律变化 已有研究表明，雌激素调节血管对褪黑素的敏感性。 PI将决定褪黑素是否会导致脑收缩 通过MT1的动脉和通过MT2受体的扩张。性的影响， 跨壁压、动脉大小和内皮因子 调查过了。PI还将测试扩张器是否通过MT2反应 雌激素暴露和使用RT-PCR可优先增强受体 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 经典雌激素受体拮抗剂和雌激素 受体基因敲除小鼠将被用来测试该受体是否 对脑血管反应性的影响。鉴于其巨大的影响， 激素替代疗法，性腺类固醇影响的知识 而褪黑激素对大脑循环是必不可少的。

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.