This proposal will examine the hypothesis that the metabolic abnormalities of glucose metabolism that characterize diabetes (ie, advanced glycosylation reactions, de novo synthesis of diglyceride) lead to alterations in expression and/or nature of extracellular matrix proteins which adversely affect mechanotransduction in arterioles. However, the same metabolic disturbances potentiate the response of vascular smooth muscle to contractile agonists. The experiments proposed will consider the effects of diabetes on both mecahnotransduction and pharmacomechanical coupling in microvascular smooth muscle. The investigator proposes to test this hypothesis on several levels. Studies will utilize the streptozotocin-induced diabetic rat model and normal controls as well as experimental groups receiving insulin or aminoguanidine treatment. In vivo measurements of arteriolar blood pressure will be performed to examine the effect of experimental diabetes on local blood pressure control. The effect of experimental diabetes on the mechanical properties of resistance vessels will also be evaluated in isolated in vitro preparations of arterioles. Isolated arteriolar preparations will be used for immunohistochemical and in situ hybridization analysis of diabetes induced alterations in the vessel wall matrix proteins, and to determine the possible role such changes in impaired mechanotransduction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054810-04
Application #
2714104
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1995-07-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Eastern Virginia Medical School
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Norfolk
State
VA
Country
United States
Zip Code
23501
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Wesselman, J P; Dobrian, A D; Schriver, S D et al. (2001) Src tyrosine kinases and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases mediate pressure-induced c-fos expression in cannulated rat mesenteric small arteries. Hypertension 37:955-60
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Tulis, D A; Prewitt, R L (1998) Medial and endothelial platelet-derived growth factor A chain expression is regulated by in vivo exposure to elevated flow. J Vasc Res 35:413-20
Parker, S B; Wade, S S; Prewitt, R L (1998) Pressure mediates angiotensin II-induced arterial hypertrophy and PDGF-A expression. Hypertension 32:452-8
Allen, S P; Wade, S S; Prewitt, R L (1997) Myogenic tone attenuates pressure-induced gene expression in isolated small arteries. Hypertension 30:203-8