Diabetes, Estrogen and Endothelial Dysfunction

糖尿病影响全世界超过3亿人，并且糖尿病患者的数量是 预计在20年内将增长50%以上。心血管疾病（CVD）是导致 糖尿病患者的死亡率和发病率，以及关键的早期步骤，内皮功能障碍， 动脉粥样硬化和随后的心血管并发症的发展。CVD的风险是 绝经前女性比年龄匹配的男性低。这种差异消失在 绝经后数年，并推测与女性性激素水平降低有关， 尤其是雌激素然而，绝经前女性糖尿病患者不仅失去 这种基于性别的心血管保护，他们实际上经历了更高的相对风险心血管疾病相比， 这表明糖尿病消除了雌激素的一些有益作用。鉴于这种 流行病学证据，问题是什么机制的基础上失去性- 糖尿病女性介导的血管保护作用。本提案将探讨性基丧失的基础 心血管保护我们的目标是专门调查雌激素介导的信号事件相关的 与糖尿病和非糖尿病大鼠以及人内皮细胞中的血管张力和内皮功能 细胞暴露于正常或高浓度的葡萄糖。我们最近报道了性别差异， 与1型糖尿病（T1 D）内皮功能障碍的关系。然而，2型糖尿病（T2 D）的病理生理 可能与T1 D中所见的不同，并且已知T2 D的发病率在全球范围内迅速增加。 因此，我们建议使用一种已建立的方法来检查肠系膜和肾动脉的血管功能。 肥胖诱导的T2 D动物模型，Zucker糖尿病肥胖（ZDF）大鼠。我们还将首次描述， 新型T2 D模型（UC Davis-T2 D Mellitus，UCD-T2 DM）中的血管功能。UCD-T2 DM大鼠似乎 更接近人类的情况，分享疾病的所有关键特征。我们打算测试 核心假设是糖尿病由于改变了雌激素的血管保护作用， 雌激素介导的与内皮源性舒张血管活性物质释放/生物利用度相关的信号传导事件 和/或限制因素。我们进一步假设，糖尿病引起的蛋白质丢失的分子基础， 血管保护作用涉及雌激素调节的以下调节的改变：1） 与动脉功能相关的特定基因，和/或2）内皮细胞中的Ca 2+转运。的 该提议的新奇在于我们将1）比较T2 D新模型中的血管反应性与观察到的血管反应性 在一个已建立的T2 D模型和2）测试的假设，在时空特征的变化， Ca 2+信号可能导致糖尿病女性雌激素依赖性血管保护作用的丧失。的 这一建议的意义在于揭示可能有助于有益和 雌激素对健康和病理状况如T2 D中血管细胞信号传导的有害作用。

Diabetes mellitus affects more than 300 million persons worldwide and the number of diabetic patients is estimated to rise by more than 50% within 20 years. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in diabetic patients, and a crucial early step, endothelial dysfunction, contributes to the development of atherosclerosis and subsequent cardiovascular complications. The risk for CVD is lower in premenopausal women compared to age-matched men. This difference disappears in the postmenopausal years and is presumably related to the reduced levels of female sex hormones, in general, and estrogen, in particular. However, premenopausal women with diabetes not only lose this sex-based cardiovascular protection, they actually experience a higher relative risk of CVD compared to diabetic men, which suggests that diabetes abrogates some of the beneficial effects of estrogen. Given this epidemiological evidence, the question arises as to what mechanisms underlie the loss of sex- mediated vasoprotection in diabetic women. This proposal will explore the basis for the loss of sex-based cardiovascular protection. We aim specifically to investigate estrogen-mediated signaling events associated with vascular tone and endothelial function in diabetic and non-diabetic rats, as well as in human endothelial cells exposed to normal or high concentrations of glucose. We recently reported sex differences with regard to endothelial dysfunction in type 1 diabetes (T1D). However, the pathophysiology of Type 2 diabetes (T2D) may differ from that seen in T1D, and it is known that the incidence of T2D is rapidly increasing worldwide. Therefore, we propose to examine vascular function in mesenteric and renal arteries using an established obesity-induced T2D animal model, the Zucker diabetic fatty (ZDF) rat. We will also characterize, for the first time, the vascular function in a novel model of T2D (UC Davis-T2D Mellitus, UCD-T2DM). UCD-T2DM rats appear to more closely resemble the human condition, sharing all of the key features of the disease. We intend to test the central hypothesis that diabetes abolishes the vasoprotective actions of estrogen due to an alteration of estrogen-mediated signaling events associated with the release/bioavailability of endothelium-derived relaxing and/or constricting factors. We further hypothesize that the molecular basis for the diabetes-induced loss of vasoprotection involves an alteration in estrogen-modulated regulation of 1) the activity and expression of specific genes that are associated with arterial function, and/or 2) Ca2+ transport in the endothelial cells. The novelty of this proposal is that we will 1) compare vascular reactivity in a novel model of T2D to that observed in an established model of T2D and 2) test the hypothesis that changes in the spatiotemporal characteristics of Ca2+ signaling may contribute to the loss of estrogen-dependent vasoprotection in diabetic females. The significance of this proposal lies in the uncovering mechanisms that may contribute to the beneficial and detrimental effects of estrogen on vascular cell signaling in healthy and pathological conditions such as T2D.