Diabetes mellitus (DM) is increasingly widespread and is a risk factor for development of peripheral vascular disease, a debilitating condition impacting 60 million Americans. With the concomitant development of additional complicating factors, including obesity, hypertension and dyslipidemia, a multi-pathology state develops: the metabolic Syndrome X. The obese Zucker rat (OZR) provides an excellent model for examining the impact of Syndrome X on the peripheral microcirculation, as owing to chronic hyperphagia, OZR sequentially develop type II DM, hypertriglyceridemia, and moderate hypertension. However, the impact of these developing pathologies on peripheral microcirculatory structure and function remains unclear. The proposed experiments will employ multiple levels of spatial resolution, ranging from measurements of enzyme expression and activity, through isolated microvessels, to perfused skeletal muscle for the examination of the effects of development of Syndrome X on skeletal muscle blood flow. Subsequent to the determination of the temporal development of Syndrome X and the resulting alterations to the peripheral microcirculation, further experiments will determine the effectiveness of chronic exercise and treating the individual disease components of Syndrome X on the structure and function of the microcirculation. These experiments will employ the OZR model of Syndrome X to determine consequences of the development of multi-component pathology on altered: 1) skeletal muscle arteriolar reactivity, 2) structure of individual microvessels and microvascular networks, and 3) perfusion and performance of in situ blood-perfused skeletal muscle. The completion of the experiments proposed in this application will allow for a fuller, more integrated understanding of the microcirculatory complications associated with Syndrome X and the ability to ameliorate developing impairments in the Zucker rat than presently exists. It is the applicant's contention that this knowledge can only be effectively garnered by extracting multiple phenotypes, at numerous levels of resolution from individual rats exhibiting Syndrome X and under conditions where the manifestation of Syndrome X is manipulated experimentally. From this base, future experiments can be developed which will target specific sites of impairment and control for the prevention and amelioration of the microcirculatory impairments associated with this debilitating pathological condition.
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