Peripheral Vasodilation in Obese Humans

肥胖人群的外周血管舒张

基本信息

批准号：
8185406
负责人：
WILLIAM G SCHRAGE
金额：
$ 60.36万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8185406
关键词：
Accounting Activities of Daily Living Acute Address Adult Age Aging Animal Model Ants Arteries Biological Availability Biopsy Blood Vessels Blood flow Body Weight decreased Cardiovascular Diseases Chronic Clinical Data Detection Development Diabetes Mellitus Disease Disease Progression Doppler Ultrasound Drug Delivery Systems Elderly Endothelial Cells Endothelium Environment Enzymes Epidemic Event Exercise Exercise Tolerance Exhibits Functional disorder Goals Health Health Care Costs Human Hyperglycemia Hypertension Impairment Infusion procedures Insulin Resistance Intervention Limb structure Link Measures Mechanics Mediating Metabolic Metabolic Diseases Metabolic syndrome Microcirculation Molecular Muscle Nitric Oxide Obesity Obesity associated disease Obstructive Sleep Apnea Oxidants Pathway interactions Patients Peripheral Peripheral Resistance Pharmaceutical Preparations Phenotype Physical activity Physiological Physiology Play Process Prophylactic treatment Prostaglandins Protocols documentation Public Health Quality of life Rattus Reactive Oxygen Species Recovery Regulation Research Rest Risk Role Sampling Signal Transduction Skeletal Muscle Staging Testing Time Vasoconstrictor Agents Vasodilation Vasodilator Agents age effect base cardiovascular risk factor combat constriction design diet and exercise disease diagnosis emerging adult glucose uptake improved improved functioning novel novel therapeutics pre-clinical premature programs relating to nervous system response restoration therapeutic target vasoconstriction young adult

项目摘要

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. PUBLIC HEALTH RELEVANCE: Obese adults exhibit poor exercise capacity which reduces quality of life and increases cardiovascular risk. The goal of this application is to understand the contribution of impaired blood vessel function to poor blood flow and increased cardiovascular risk in obese adults. The findings of how obesity changes blood vessel function and exercise responses will provide ideas on how to limit disease progression, or improve function, in an effort to restore the quality of life of obese adults-as well as other patients with obesity-related diseases.

描述（由申请人提供）：该研究计划的总体目标是调查与肥胖相关的微血管功能变化，从而引发心血管疾病过程。预计肥胖成年人口的不断增长将在未来几十年内造成巨大的公共健康负担。骨骼肌负责人类外周阻力和葡萄糖摄取的大部分。肌肉血管舒张减少可能会导致高血压，并为高血糖奠定基础——这都是代谢综合征和糖尿病的标志。因此，肥胖人群的肌肉血流量较低可能会导致运动能力下降，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，研究年轻的肥胖“代谢健康”成年人（18-35 岁），不考虑年龄、代谢综合征或糖尿病的混杂影响。一般假设是，肥胖通过增加活性氧（ROS）、减少血管舒张信号和增加血管收缩信号来损害内皮依赖性扩张（EDD）和运动血管舒张。我们的初步数据表明年轻肥胖成年人表现出 EDD 和运动血管舒张减少，而急性 ROS 清除可以改善这两者。我们将通过动脉药物输注来检验我们的假设，以测试瘦人和肥胖人群的 EDD 机制。我们将使用类似的方法来测试动态运动期间控制血流的血管机制。接下来，我们将测试饮食和运动干预前后的 EDD 和运动血管反应，从而确定体力活动或体重减轻是否在血管改善中发挥更大作用。最后，我们将从这些相同受试者中采集动脉内皮细胞样本，以确定随肥胖而变化的分子途径作为潜在的治疗靶点。这些研究整合了生理学、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支持我们的假设，并设计了一套补充目标，将妥善解决我们的研究问题。将采用多学科、最先进的方法来实现这些目标，这将为肥胖人群血流量减少的 EDD 和运动机制提供基本的机制理解。我们的新发现将指导肥胖症和其他疾病（包括阻塞性睡眠呼吸暂停、代谢综合征和糖尿病）的新治疗策略的开发。公共卫生相关性：肥胖成年人的运动能力较差，这会降低生活质量并增加心血管风险。该应用的目的是了解血管功能受损对肥胖成人血流不良和心血管风险增加的影响。关于肥胖如何改变血管功能和运动反应的研究结果将为如何限制疾病进展或改善功能提供思路，以努力恢复肥胖成年人以及其他患有肥胖相关疾病的患者的生活质量。