Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes.
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.


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 x kg(-1) x day(-1)), or ET(B) receptor antagonist A-192621 (15 mg x kg(-1) x 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.
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia, USA.
Kamakshi
K
Sachidanandam
Vera
V
Portik-Dobos
Alex K
AK
Harris
Jim R
JR
Hutchinson
Erin
E
Muller
Maribeth H
MH
Johnson
Adviye
A
Ergul
D000818:Animals; D001158:Arteries / Q000502:physiology; D000077868:Atrasentan; D017364:Collagenases / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D014655:Vascular Resistance / Q000502:physiology*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007328:Insulin; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011994:Recombinant Proteins; D017364:Collagenases; D020782:Matrix Metalloproteinases; D000077868:Atrasentan