Mechanisms of exertional hypertension and vascular dysfunction

描述(由申请人提供)：一氧化氮(NO)依赖的血管功能受损是心血管疾病发展的先兆，也是动脉粥样硬化发展的始动事件。由于血管内皮细胞一氧化氮的改善，有氧运动长期以来一直与较低的心脏病发病率和死亡率有关。虽然阻力运动对NO生物利用度的影响知之甚少，但流行病学证据表明，举重训练可能会减少心脏事件。然而，单次阻力运动的表现也是一种生理应激，会引起炎症反应和急性高血压，从而可能改变内皮健康。初步数据表明，在久坐不动的受试者中，活性氧物种(ROS)介导了急性举重过程中的内皮功能障碍，但条件举重者却没有。这表明慢性阻力运动可以保护血管内皮的健康。该建议的目的是确定运动诱导的保护机制，以对抗急性举重引起的内皮功能障碍。总的假设是，慢性阻力运动保护内皮功能障碍，并降低在单次举重训练后产生的ROS诱导的NO生物利用度。该提案将检验以下假设：1)阻力和有氧训练运动员在单次举重训练后免受ROS和内皮功能障碍炎症介质的影响；2)血管ROS产生机制介导了举重导致的静坐受试者的内皮功能障碍。这项研究建议与职业发展计划相结合，将申请者在基础血管生物学方面的优势与人类血管健康评估结合在一起。候选人肖恩·菲利普斯博士是威斯康星医学院的助理教授。他的职业目标是成为人类血管生物学领域的一名独立翻译研究员，这一提议将为这一过渡提供一个支持性的研究环境和机构支持。职业发展计划利用最先进的血管技术和教学培训，旨在调查临床相关问题，同时建立在他之前的物理治疗临床培训和血管生物学博士培训的基础上。大卫·古特曼博士是一位知名的翻译研究员，他将在候选人独立研究生涯的初始阶段提供指导。

DESCRIPTION (provided by applicant): Impaired nitric oxide (NO) dependent vascular function precedes the development of cardiovascular disease and is an initiating event in the development of atherosclerosis. Aerobic exercise has long been associated with lower morbidity and mortality from heart disease owing to improvements in vascular endothelial NO. While much less is known about the effects of resistance exercise on NO bioavailability, epidemiological evidence indicates that weight training may reduce cardiac events. However, performance of a single bout of resistance exercise is also a physiologic stressorthat elicits an inflammatory response and acute hypertension that may alter endothelial health. Preliminary data suggest that reactive oxygen species (ROS) mediate endothelial dysfunction during acute weight lifting in sedentary subjects but not conditioned weight lifters suggesting chronic resistance exercise protects vascular endothelial health. The goal of this proposal is to determine the mechanism of exercise induced protection against acute weight lifting induced endothelial dysfunction. The overall hypothesis is that chronic resistance exercise protects against endothelial dysfunction and reduced NO bioavailibility induced by ROS generation following a single weight lifting session. The proposal will test the following hypotheses that: 1) Resistance and aerobic trained athletes are protected from ROS and inflammatory mediators of endothelial dysfunction in response to a single weight lifting session; and 2) Vascular ROS generating mechanisms mediate endothelial dysfunction induced by weight lifting in sedentary subjects. This research proposal coupled with the career development program integrates the strengths of the applicant in fundamental vascular biology with assessment of human vascular health. The candidate Dr. Shane Phillips is an Assistant Professor at the Medical College of Wisconsin. His career goal is to become an independent translational investigator in the field of human vascular biology and this proposal will provide a supportive research environment as well as institutional support for this transition. The career development plan utilizes state of the art vascular techniques and didactic training geared toward the investigation of clinically relevant questions while building on his previous clinical training in physical therapy and doctoral training in vascular biology. Dr. David Gutterman, an established translational researcher, will provide mentorship during the initial stages of the candidates' independent research career.