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Evidence for Vasculoprotective Effects of ET_B Receptors in Resistance Artery Remodeling in Diabetes

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

Address correspondence and reprint requests to Adviye Ergul, MD, PhD, Medical College of Georgia, Dept. of Physiology CA-2094, Augusta, GA 30912. E-mail: aergul{at}mcg.edu

Abbreviations: ECM, extracellular matrix; ET, endothelin; M/l, media-to-lumen; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of MMP; VSMC, vascular smooth muscle cell

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.

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, ET_A receptor antagonist atrasentan (5 mg · kg^–1 · day^–1), or ET_B receptor antagonist A-192621 (15 mg · kg^–1 · day^–1) 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 ET_A antagonism improved enzyme activity, ET_B blockade further reduced collagenase levels. Accordingly, collagen deposition was augmented in GK rats, 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 ET_A receptors, and ET_B receptors provide vasculoprotective effects.

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