Peripheral Vasodilation in Obese Humans

描述(由申请人提供)： 这项研究计划的总体目标是调查启动心血管疾病过程的与肥胖相关的微血管功能变化。预计在接下来的几十年里，越来越多的肥胖成年人将造成巨大的公共卫生负担。骨骼肌是人体外周阻力和葡萄糖摄取的主要来源。肌肉血管扩张减少可能会导致高血压，并为高血糖奠定基础--这两种症状都是代谢综合征和糖尿病的特征。因此，肥胖人群的肌肉血流量低可能会导致运动量减少，这反过来又为糖尿病等长期心血管疾病的发展奠定了基础。我们建议在肥胖的负面影响发挥其全部负面影响之前，研究不受年龄、代谢综合征或糖尿病影响的年轻肥胖“代谢健康”成年人(18-35岁)。一般的假说是，肥胖通过增加活性氧(ROS)、减少血管扩张信号和增加血管收缩信号来损害内皮依赖性扩张(EDD)和运动血管扩张。我们的初步数据表明，年轻肥胖成年人表现出EDD和运动血管扩张减少，而急性清除ROS可以改善这两个方面。我们将通过动脉输注药物来验证我们的假设，以测试瘦人和肥胖者的EDD机制。我们将使用类似的方法来测试动态运动中控制血液流动的血管机制。接下来，我们将在饮食和运动干预前后测试EDD和运动血管反应，从中我们可以区分体育活动或减肥在血管改善中起到的更大作用。最后，我们将从这些受试者身上采集动脉内皮细胞样本，以确定随着肥胖而变化的分子通路，作为潜在的治疗靶点。这些研究结合了生理学、药理学和分子方法来检验我们的假设。我们有几个令人兴奋的初步发现来支持我们的假设，并设计了一套补充的目标，这将合理地解决我们的研究问题。将使用多学科、最先进的方法来实现这些目标，这将提供对EDD和运动机制的基本理解，这些机制负责肥胖人类的血液流动减少。我们的新发现将指导开发针对肥胖和其他疾病的新治疗策略，包括阻塞性睡眠呼吸暂停、代谢综合征和糖尿病。

DESCRIPTION (provided by applicant): The overall goal of this research program is to investigate the obesity-related changes in microvascular function that initiate the cardiovascular disease process. The growing population of obese adults is predicted to create a large public health burden in the next few decades. Skeletal muscle accounts for the majority of peripheral resistance and glucose uptake in humans. Decreased muscle vasodilation likely contributes to hypertension and sets the stage for hyperglycemia-both hallmarks of metabolic syndrome and diabetes. Thus, low muscle blood flow in obese humans may contribute to reduced exercise capacity-this in turn sets the stage for development of long-term cardiovascular diseases like diabetes. We propose to study younger obese "metabolically health" adults (18-35 yrs), without confounding effects of age, metabolic syndrome, or diabetes- before the negative effects of obesity can exert their full negative impact. The general hypothesis is that obesity impairs endothelium dependent dilation (EDD) and exercise vasodilation via increased reactive oxygen species (ROS) and reductions in vasodilator signals and increased vasoconstrictor signals. Our preliminary data suggest young obese adults exhibit reduced EDD and exercise vasodilation, and acute ROS scavenging improves both. We will test our hypotheses by arterial drug infusion to test EDD mechanisms in lean and obese humans. We will use similar approaches to test vascular mechanisms controlling blood flow during dynamic exercise. Next, we will test EDD and exercise vascular responses before and after a diet and exercise intervention, where we can parcel out whether physical activity or weight loss plays a larger role in vascular improvements. Finally, we will sample artery endothelial cells from these same subjects to identify molecular pathways that change with obesity as potential therapeutic targets. These studies integrate physiologic, pharmacologic, and molecular approaches to test our hypotheses. We have several exciting preliminary findings that support our hypotheses, and have designed a complementary set of Aims the will soundly address our research questions. A multi-disciplinary, state-of-the-art approach will be used to pursue these aims, which will provide fundamental mechanistic understanding of EDD and exercise mechanisms responsible for reduced blood flow in obese humans. Our novel findings will guide the development of novel therapeutic strategies for obesity and other diseases, including obstructive sleep apnea, metabolic syndrome and diabetes.