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.
