OBJECTIVE-Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/l) ratio, contributes to the development of microvascular complications in diabetes. Matrix metalloproteinases (MMPs) play an important role in the regulation of extracellular matrix (ECM) turnover and vascular remodeling. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which makes it a likely candidate for a key role in vascular complications of diabetes. Thus, this study investigated the regulation of MMP activity of resistance arteries under mild-to-moderate diabetes conditions, as seen in type 2 diabetes, and the relative role of ET receptors in this process. C ardiovascular complications contribute to the increased morbidity and mortality in type 2 diabetes. Pathological changes in vascular function and structure underlie these complications. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which make it a likely candidate for a key role in vascular complications of diabetes. A significant correlation has been observed between plasma ET-1 levels and diabetes complications (1,2). ET A receptor antagonism prevents mesenteric vascular hypertrophy in type 1 diabetes (3). Fukuda et al. (4) reported that blockade of ET-1 action inhibits aortic extracellular matrix (ECM) deposition. We showed that ET-1 levels are elevated and that an ET A antagonist prevents ECM deposition and MMP activation in middle cerebral arteries but not in the kidney of Goto-Kakizaki (GK) rats-a nonobese type 2 diabetes model (5,6). ET-1 mediates its diverse effects via distinct G protein-coupled receptor subtypes ETB AB and ETB BB . While these past studies indicate the involvement of the ET A receptor subtype in mediating detrimental effects of ET-1, the role of ET B receptors in diabetes-induced changes in the vasculature remains unknown. ETB AB receptors, localized mainly on vascular smooth muscle cells (VSMCs), are responsible for the vasocontractile and proliferative response to ET-1 (7). Endothelial ETB B receptors mediate vasodilatation, whereas VSMC ET B receptors can also lead to vasoconstriction in certain vascular beds (7). This duality of function of ETB B receptors underscores the importance of binding and function of both ET receptor subtypes. Especially given that inhibition of the ETB BB receptor system in a knockout mouse model or pharmacological blockade by an ETB BB antagonist leads to enhanced intimal hyperplasia observed in carotid arteries after injury induced by ligation, suggesting a vasculoprotective effect (8), the question remains whether ET B receptors contribute to or balance detrimental effects of ET A receptor activation in diabetic vascular remodeling.
RESEARCH DESIGN AND METHODS-VesselVascular ECM displays a very dynamic equilibrium where there is constant synthesis, degra...