Americans currently live in an epidemic of obesity and associated risk factors, a condition referred to as the metabolic Syndrome X. Peripheral Vascular Disease (PVD) is 1 of the most debilitating afflictions in patients with Syndrome X, which is the combined presentation of obesity, insulin resistance, hypertension and Type II diabetes. The factors that lead to PVD remain poorly understood. The goal of the current application is to use an animal model of Syndrome X to identify the causes and mechanisms of perturbations in the skeletal muscle microcirculation that may predispose to PVD. Preliminary data identify 2 major defects in skeletal muscle microvessels: An augmented reactivity to a-adrenergic stimulation and a microvascular remodeling to smaller, stiffer arterioles.
Aim 1 of this proposal will test the hypothesis that the insulin resistance associated with Syndrome X is the underlying cause of adrenergic hypercontractility in the hindlimb circulation and that the mechanism of this augmentation is an increase in a-adrenoceptor expression.
Aim 2 will test the hypothesis that hindlimb blood flow is limited under both physiologic and pharmacologic conditions in Syndrome X and this limitation is alleviated by inhibition of a-adrenergic hypercontractility.
Aim 3 will test the hypothesis that remodeling of the hindlimb microcirculation in Syndrome X reflects low flow brought on by augmented vasoconstriction, not elevated pressure and that this remodeling is mediated by the activation of MMPs and expression of angiostatins. We further hypothesize that exercise can improve remodeling by chronically increasing blood flow to skeletal muscle. Taken together, these experiments will identify novel mechanisms of vascular dysfunction in a model of the metabolic Syndrome X and may help identify new therapeutic targets and strategies for treatment of peripheral vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076533-03
Application #
7162629
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2005-01-15
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$305,078
Indirect Cost
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Belin de Chantemele, Eric J; Stepp, David W (2012) Influence of obesity and metabolic dysfunction on the endothelial control in the coronary circulation. J Mol Cell Cardiol 52:840-7
Osmond, Jessica M; Mintz, James D; Stepp, David W (2010) Preventing increased blood pressure in the obese Zucker rat improves severity of stroke. Am J Physiol Heart Circ Physiol 299:H55-61
Ali, M Irfan; Ketsawatsomkron, Pimonrat; Belin de Chantemele, Eric J et al. (2009) Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. Circ Res 105:1013-22
Romanko, Olga P; Ali, M Irfan; Mintz, James D et al. (2009) Insulin resistance impairs endothelial function but not adrenergic reactivity or vascular structure in fructose-fed rats. Microcirculation 16:414-23
Osmond, Jessica M; Mintz, James D; Dalton, Brian et al. (2009) Obesity increases blood pressure, cerebral vascular remodeling, and severity of stroke in the Zucker rat. Hypertension 53:381-6
Belin de Chantemèle, Eric J; Muta, Kenjiro; Mintz, James et al. (2009) Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. Circulation 120:753-63
Stepp, David W; Boesen, Erika I; Sullivan, Jennifer C et al. (2007) Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat. Am J Physiol Heart Circ Physiol 293:H2537-42
Prakash, Rajan; Mintz, James D; Stepp, David W (2006) Impact of obesity on coronary microvascular function in the Zucker rat. Microcirculation 13:389-96