Endothelial endothelin B receptor-mediated prevention of cerebrovascular remodeling is attenuated in diabetes because of up-regulation of smooth muscle endothelin receptors

Aisha I. Kelly-Cobbs, Alex K. Harris, Mostafa M. Elgebaly, Weiguo Li, Kamakshi Sachidanandam, Vera Portik-Dobos, Maribeth Johnson, Adviye Ergul

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Structure and function of the cerebrovasculature is critical for ischemic stroke outcome. We showed that diabetes causes cerebrovascular remodeling by activation of the endothelin A (ET A) receptors. The goal of this study was to test the hypotheses that vasculoprotective endothelial ET B receptors are decreased and pharmacological inhibition of the ET B receptor augments vascular remodeling of middle cerebral arteries (MCAs) in type 2 diabetes. MCA structure, matrix metalloprotease (MMP) activity, and matrix proteins as well as ET A and ET B receptor profiles were assessed in control Wistar and diabetic Goto-Kakizaki rats treated with vehicle, the ET B receptor antagonist (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-[(2,6-diethylphenyl)amino]-2-oxoethyl] -2-(4-propoxyphenyl)pyrrolidine-3-carboxylic acid (A192621) (30 mg/kg/day), or the dual ET receptor antagonist bosentan (100 mg/kg/day) for 4 weeks. Diabetes increased vascular smooth muscle (VSM) ET A and ET B receptors; the increase was prevented by chronic bosentan treatment. MCA wall thickness was increased in diabetes, and this was associated with increased MMP-2 activity and collagen deposition but reduced MMP-13 activity. Because of up-regulation of VSM ET receptors in diabetes, selective ET B receptor antagonism with A192621 blunts this response, and combined ET A and ET B receptor blockade with bosentan completely prevents this response. On the other hand, A192621 treatment augmented remodeling in control animals, indicating a physiological protective role for this receptor subtype. Attenuation of changes in ET receptor profile with bosentan treatment suggests that ET-1 has a positive feedback on the expression of its receptors in the cerebrovasculature. These results emphasize that ET receptor antagonism may yield different results in healthy and diseased states.

Original languageEnglish (US)
Pages (from-to)9-15
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume337
Issue number1
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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