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Diabetes Publish Ahead of Print published online ahead of print August 1, 2007
DOI: 10.2337/db07-0426
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Original Research

Evidence for Vasculoprotective Effects of ETB Receptors In Resistance Artery Remodeling In Diabetes

Kamakshi Sachidanandam1, Vera Portik-Dobos1, Alex K. Harris1, Jim R. Hutchinson1, Erin Muller1, Maribeth H. Johnson2, and Adviye Ergul1,,3

1From the Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy
2Departments of Biostatistics and
3Physiology, Medical College of Georgia, Augusta, Georgia

Correspondence: aergul{at}mcg.edu

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 ECM turnover and vascular remodeling. Vasoactive factor endothelin-1 (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 diabetic conditions as seen in Type 2 diabetes and the relative role of ET receptors in this process.

Research Design and Methods:Vessel structure, MMP activity and ECM proteins were assessed in control Wistar and diabetic Goto-Kakizaki (GK) rats treated with vehicle, ETA receptor antagonist Atrasentan (5 mg/kg/day) or ETB receptor antagonist A-192621 (15 mg/kg/day) for 4 weeks.

Results:M/L ratio was increased in diabetes. Atrasentan prevented this increase whereas A-192621 caused further thickening of the medial layer. Increased MMP-2 activity in diabetes was prevented by Atrasentan treatment. Collagenase activity was significantly decreased in diabetes and while ETA antagonism improved enzyme activity, ETB blockade further reduced collagenase levels. Accordingly, collagen deposition was augmented in GKs which was reversed by Atrasentan but exacerbated with A-192621.

Conclusions:ET-1 contributes to the remodeling of mesenteric resistance arteries in diabetes via activation of ETA receptors and that ETB receptors provide vasculoprotective effects.


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Copyright © 2007 by the American Diabetes Association.