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

  1. Kamakshi Sachidanandam1,
  2. Vera Portik-Dobos2,
  3. Alex K. Harris1,
  4. Jim R. Hutchinson2,
  5. Erin Muller2,
  6. Maribeth H. Johnson3 and
  7. Adviye Ergul1,2
  1. 1Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia
  2. 2Department of Physiology, Medical College of Georgia, Augusta, Georgia
  3. 3Department of Biostatistics, Medical College of Georgia, Augusta, Georgia
  1. 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

Abstract

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, ETA receptor antagonist atrasentan (5 mg · kg−1 · day−1), or ETB 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 ETA antagonism improved enzyme activity, ETB 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 ETA receptors, and ETB receptors provide vasculoprotective effects.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 1 August 2007. DOI: 10.2337/db07-0426.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received March 28, 2007.
    • Accepted July 27, 2007.
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  1. Diabetes vol. 56 no. 11 2753-2758
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