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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064668-03
Application #
6966333
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Jones, Teresa L Z
Project Start
2004-09-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$257,180
Indirect Cost
Name
West Virginia University
Department
Physiology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Frisbee, Jefferson C; Butcher, Joshua T; Frisbee, Stephanie J et al. (2016) Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol 310:H488-504
Chantler, Paul D; Shrader, Carl D; Tabone, Lawrence E et al. (2015) Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability. Microcirculation 22:435-45
Butcher, Joshua T; Stanley, Shyla C; Brooks, Steven D et al. (2014) Impact of increased intramuscular perfusion heterogeneity on skeletal muscle microvascular hematocrit in the metabolic syndrome. Microcirculation 21:677-87
Butcher, Joshua T; Goodwill, Adam G; Stanley, Shyla C et al. (2013) Differential impact of dilator stimuli on increased myogenic activation of cerebral and skeletal muscle resistance arterioles in obese zucker rats. Microcirculation 20:579-89
Butcher, Joshua T; Goodwill, Adam G; Stanley, Shyla C et al. (2013) Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease? Am J Physiol Heart Circ Physiol 304:H547-58
Frisbee, Jefferson C; Goodwill, Adam G; Butcher, Joshua T et al. (2011) Divergence between arterial perfusion and fatigue resistance in skeletal muscle in the metabolic syndrome. Exp Physiol 96:369-83
Frisbee, Jefferson C; Wu, Fan; Goodwill, Adam G et al. (2011) Spatial heterogeneity in skeletal muscle microvascular blood flow distribution is increased in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 301:R975-86
Wu, Fan; Beard, Daniel A; Frisbee, Jefferson C (2011) Computational analyses of intravascular tracer washout reveal altered capillary-level flow distributions in obese Zucker rats. J Physiol 589:4527-43
Stapleton, Phoebe A; Goodwill, Adam G; James, Milinda E et al. (2010) Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice. Microcirculation 17:47-58
Frisbee, Jefferson C; Goodwill, Adam G; Stapleton, Phoebe A et al. (2010) Aspirin resistance with genetic dyslipidemia: contribution of vascular thromboxane generation. Physiol Genomics 42:331-41

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