TY - JOUR
T1 - Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes
AU - Sachidanandam, Kamakshi
AU - Portik-Dobos, Vera
AU - Harris, Alex K.
AU - Hutchinson, Jim R.
AU - Muller, Erin
AU - Johnson, Maribeth H.
AU - Ergul, Adviye
PY - 2007/11
Y1 - 2007/11
N2 - 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 ET A 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.
AB - 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 ET A 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.
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U2 - 10.2337/db07-0426
DO - 10.2337/db07-0426
M3 - Article
C2 - 17670915
AN - SCOPUS:35748984126
SN - 0012-1797
VL - 56
SP - 2753
EP - 2758
JO - Diabetes
JF - Diabetes
IS - 11
ER -