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 language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Apr 1 2011|
ASJC Scopus subject areas
- Molecular Medicine