Mechanisms of exertional hypertension and vascular dysfunction

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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.