Microcirculation in Health and Disease

描述（由申请人提供）：我们实验室的长期目标是确定将肌肉血液流动与组织代谢状态联系起来的生理机制。作为对运动的反应，骨骼肌血流量通过小动脉的功能性血管扩张而急剧增加。我们已经证明花生四烯酸代谢物在控制肌肉血流中很重要。当前提案中的研究将扩展这些研究，并确定慢性运动改善肥胖患者血管舒张功能的机制。在美国，肥胖正以惊人的速度增长，是各种心血管疾病的主要危险因素。美国国立卫生研究院已经启动了临床试验，以确定运动训练是否能改善患有2型糖尿病和高血压的人的心血管健康，这两种疾病在肥胖中普遍存在。肥胖的人在运动后增加肌肉血流量的能力受损，而这种异常血流量增加（功能性充血）的机制尚不清楚。功能性充血受损可能会阻止肥胖患者进行适当的运动，而运动是一种已知的改善血糖、血脂和体重控制的疗法。因此，更好地了解慢性运动训练改善肥胖患者功能性充血的机制是很重要的。我们最近的研究表明，在肥胖人群中，花生四烯酸代谢发生了改变，导致急性运动时血流反应受损。我们还证明了慢性运动训练可以改善肥胖动物模型的功能性血管舒张反应。基于我们已发表的和初步的数据，本研究的总体目标是验证慢性运动训练可以通过改善PGI2血管舒张反应和降低血栓素血管收缩反应来改善血管舒张的中心假设。我们认为花生四烯酸代谢的这些改变是由于高血糖/高脂血症引起的活性氧增加。拟议的研究将利用体内和体外微循环技术，为慢性运动训练改善肥胖患者功能性血管舒张反应的机制提供新的重要见解。公共卫生相关性：肥胖在美国正以惊人的速度增长，并且是多种心血管疾病的主要危险因素。肥胖的人在运动后增加肌肉血流量的能力受损，这可能会阻止肥胖患者进行适当的运动，而这种运动已知可以改善与肥胖相关的血糖、血脂和体重升高。因此，更好地了解慢性运动训练改善肥胖患者肌肉血流量的机制是很重要的。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to define the physiological mechanisms linking muscle blood flow to the metabolic state of the tissue. In response to exercise, skeletal muscle blood flow increases dramatically through a functional vasodilation of the arterioles. We have demonstrated that arachidonic acid metabolites are important in the control of muscle blood flow. The studies in the current proposal will extend these studies and determine the mechanisms by which chronic exercise improves functional vasodilatory in obesity. Obesity is increasing at an alarming rate in the United States and is a major risk factor for a variety of cardiovascular diseases. NIH has initiated clinical trials to determine if exercise training improves cardiovascular health in persons who have both Type 2 diabetes and hypertension, conditions that are prevalent in obesity. Obese humans have an impaired ability to increase muscle blood flow in response to exercise, and the mechanisms underlying this abnormal increase in blood flow (functional hyperemia) are unclear. An impaired functional hyperemia could potentially prevent the obese patient from adequate exercise, a therapy known to improve glucose, lipid and weight control. Therefore, a better understanding of the mechanisms underlying improved functional hyperemia by chronic exercise training in obesity is important. Our recent work has demonstrated that, in obesity, there is an altered arachidonic acid metabolism, resulting in an impaired blood flow response to acute exercise. We have also demonstrated that chronic exercise training improves functional vasodilatory responses in an animal model of obesity. Based on our published and preliminary data the overall goal of this proposal is to test the central hypothesis that chronic exercise training will improve functional vasodilation through improvements in PGI2 vasodilatory responses and decreases in thromboxane vasoconstrictor responses. We propose that these alterations in arachidonic acid metabolism are due to hyperglycemic/hyperlipidemic induced increases in reactive oxygen species. The proposed studies will utilize in vivo and in vitro microcirculatory techniques to provide new and important insights into mechanisms by which chronic exercise training improves functional vasodilatory responses in obesity. PUBLIC HEALTH RELEVANCE: Obesity is increasing at an alarming rate in the United States and is a major risk factor for a variety of cardiovascular diseases. Obese humans have an impaired ability to increase muscle blood flow in response to exercise, which could prevent the obese patient from adequate exercise, a therapy known to improve the elevated glucose, lipids and body weight associated with obesity. Therefore, a better understanding of the mechanisms by which chronic exercise training improves muscle blood flow in obesity is important.