Phytoestrogens, insulin resistance and endothelial function

描述(申请人提供)：为了减少与年龄相关的血管舒缩症状和降低心血管疾病的风险，许多女性选择非处方药植物雌激素，而支持医生开出的雌激素处方。金雀异黄素是研究最多、最常见的大豆衍生植物雌激素。金雀异黄素在结构上类似于172-雌二醇，对人类血管中存在的ER2受体具有高亲和力，但对生殖器官中存在的ER1受体具有低亲和力。研究支持大豆提取的植物雌激素对血管反应性和内皮功能的有益影响。然而，在金雀异黄素治疗期间，胰岛素抵抗患者内皮依赖性扩张的预期改善程度有所减弱。该项目旨在研究染料木素对健康女性和胰岛素抵抗女性微血管反应性的影响。我们的一般假设是金雀异黄素通过一氧化氮机制改善健康女性的内皮功能，但该机制对胰岛素抵抗女性无效。我们将使用皮肤血管系统作为研究内皮功能的模型，并将使用微透析将雌二醇和染料木素直接注入皮肤，同时使用激光多普勒血流仪测量微血管血流量。我们的第一个目标将使用剂量-反应曲线来确定172-雌二醇和金雀异黄素对患有和不患有胰岛素抵抗的女性外周微血管的影响。我们假设，两种激素的注射都会增加两组女性的血流量，但对胰岛素抵抗的女性来说，血管扩张会减弱。我们的第二个目的是验证这样一个假设，即一氧化氮介导了健康女性的雌二醇和染料木素诱导的血管扩张，但不是胰岛素抵抗女性更温和的血管扩张的一个因素。女性服用染料木素和其他植物雌激素具有一定的心血管保护作用，但数据尚未明确证明这些好处。我们的研究将直接评估染料木素影响血管扩张的程度，并探讨其作用机制。此外，我们的发现将为研究染料木素和其他植物雌激素对雷诺氏病和高血压等与外周循环受损相关的其他疾病的影响提供基础。这些拟议的研究不仅将提供雌二醇、染料木素、胰岛素抵抗和内皮功能之间相互作用的机制信息，还将为未来对患有胰岛素抵抗的老年女性和男性的研究提供基础。 与公共卫生相关：为了减少血管舒缩症状和预防与年龄相关的心血管疾病风险增加，越来越多的女性选择非处方药植物雌激素(如染料木素)，转而使用医生开出的雌激素。金雀异黄素可能会改善血管功能，但不会带来与雌激素暴露相关的乳腺癌风险增加。胰岛素抵抗会增加心血管疾病的风险，也可能干扰染料木素对心血管功能的作用。因此，这些研究具有广泛的公共健康影响，因为重要的是，女性在服用染料木素时不会产生心血管保护的错误感觉。

DESCRIPTION (provided by applicant): With the goal of reducing the age-associated vasomotor symptoms and decreasing the risk of cardiovascular disease, many women choose over the counter phytoestrogens in favor of estrogens prescribed by their physicians. Genistein is the best studied and most common of the soy-derived phytoestrogens. Genistein is structurally similar to 172-estradiol and has high affinity for the ER2 receptor present in the human vasculature, but low affinity for the ER1 receptor present in reproductive organs. Studies support beneficial effects of soy-derived phytoestrogens on vascular reactivity and endothelial function. However, during genistein treatment the expected improvement in endothelial dependent dilation is attenuated in individuals with insulin resistance. This project is designed to study the impact of genistein on microvascular reactivity both in healthy women and in women with insulin resistance. Our general hypothesis is that genistein improves endothelial function through a nitric oxide mechanism in healthy women, but that this mechanism is ineffective in women with insulin resistance. We will use the cutaneous vasculature as a model to study endothelial function, and will infuse estradiol and genistein directly into the skin using microdialysis while measuring microvascular blood flow with laser Doppler flowmetry. Our first Aim will use dose-response curves to determine the 172-estradiol and genistein effects on the peripheral microvasculature in women with and without insulin resistance. We hypothesize that both hormone infusions will increase blood flow in both groups of women, but the vasodilation will be attenuated in women with insulin resistance. Our second Aim tests the hypothesis that nitric oxide mediates the estradiol and genistein-induced vasodilation in healthy women, but is not a factor in the more moderate vasodilation seen in women with insulin resistance. Women take genistein and other phytoestrogens assuming a level of cardiovascular protection, but data have not definitively demonstrated these benefits. Our studies will directly assess the extent to which genistein impacts vasodilation and examine the mechanism for its effects. Moreover, our findings will provide a basis to study the impact of genistein and other phytoestrogens on other conditions associated with compromised peripheral circulation such as Reynaud's disease and hypertension. The proposed studies will not only provide mechanistic information on the interaction between estradiol, genistein, insulin resistance and endothelial function, but will serve as a basis for future studies in older women and men with insulin resistance. PUBLIC HEALTH RELEVANCE: With the goal of reducing vasomotor symptoms and protection against the age-associated increase in cardiovascular disease risk, women are increasingly choosing over the counter phytoestrogens (such as genistein) in favor of estrogens prescribed by their physicians. Genistein may improve vascular function but not carry with it the increased breast cancer risks that have been associated with estrogen exposure. Insulin resistance increases cardiovascular disease risk, and may also interfere with the actions of genistein on cardiovascular function. Therefore, these studies have broad public health implications because it is important that women not have a false sense of cardiovascular protection while taking genistein.