Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetes.

Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto-Kakizaki (GK) rats that selective ETA receptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases (MMP), whereas selective ETB receptor blockade augments this thickening. The goal of this study was to determine the effect of combined ETA and ETB receptor blockade on resistance vessel remodeling. Vessel structure, MMP activity, and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or bosentan (100 mg/kg per day) for 4 weeks (n = 7-9 per group). Bosentan completely prevented the increase in M/L ratio and MMP-2 activity in diabetes but paradoxically increased M/L ratio and MMP activation in control animals. Collagenase (MMP-13) activity and protein levels were significantly decreased in diabetes. Accordingly, collagen deposition was augmented in GK rats. Dual ET receptor antagonism improved enzyme activity and normalized MMP-13 levels in diabetic animals but blunted MMP-13 activity in control animals. In summary, current findings suggest that diabetes-mediated remodeling of resistance arteries is prevented by dual blockade of ETA and ETB receptors and that the relative role of ET receptors in the regulation of vascular structure differs in the control and disease states.