Diabetes, Estrogen and Endothelial Dysfunction

糖尿病影响全球超过3亿人，糖尿病患者的数量是 预计在20年内上涨50%以上。心血管疾病(CVD)是主要原因 糖尿病患者死亡率和发病率的增加，以及一个关键的早期步骤，内皮功能障碍，有助于 导致动脉粥样硬化和随后的心血管并发症的发展。心血管疾病的风险是 绝经前女性与年龄匹配的男性相比更低。这种差异消失在 这可能与女性性激素水平降低有关，在 一般的，特别是雌激素。然而，绝经前患有糖尿病的女性不仅减少了 这种基于性别的心血管保护，实际上她们患心血管疾病的相对风险比 糖尿病男性，这表明糖尿病剥夺了雌激素的一些有益影响。鉴于此， 流行病学证据表明，性功能丧失的机制是什么？ 糖尿病妇女的介导性血管保护。这项建议将探索失去以性为基础的 心血管保护。我们的目标是研究雌激素介导的相关信号事件。 糖尿病和非糖尿病大鼠以及人内皮细胞的血管张力和内皮功能 暴露于正常或高浓度葡萄糖的细胞。我们最近报道了性别差异 与1型糖尿病(T1D)的内皮功能障碍有关。然而，2型糖尿病(T2D)的病理生理学 可能与T1D不同，众所周知，T2D的发病率在全球范围内迅速增加。 因此，我们建议使用已建立的一种方法来检查肠系膜动脉和肾动脉的血管功能。 肥胖诱导的T2D动物模型，Zucker糖尿病肥胖(ZDF)大鼠。我们还将首次描述， 一种新的T2D模型(UC Davis-T2D糖尿病，UCD-T2 DM)的血管功能UCD-T2 DM大鼠似乎 更接近于人类的情况，分享了这种疾病的所有关键特征。我们打算测试 中心假说，糖尿病取消雌激素的血管保护作用是由于 雌激素介导的信号转导事件与内皮舒张剂的释放/生物利用度相关 和/或限制因素。我们进一步假设，糖尿病引起的血管紧张素转换酶缺失的分子基础 血管保护涉及雌激素调节的调节的改变，1)活性和表达 与动脉功能相关的特定基因，和/或2)内皮细胞中的钙离子运输。这个 这一提议的新奇之处在于，我们将1)比较新的T2D模型中的血管反应性与观察到的血管反应性 在已建立的T2D模型中，2)检验假设在时空特征上的变化 钙信号可能是女性糖尿病患者雌激素依赖性血管保护丧失的原因之一。这个 这一建议的意义在于揭示了可能有助于 在健康和病理条件下，如T2D，雌激素对血管细胞信号的有害影响。

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.