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RECEPTORS AND SIGNALING PATHWAYS

Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes: link to endothelin-1

¹Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, ²Department of Physiology, Medical College of Georgia, Augusta, Georgia; ³Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan; and ⁴Abraxis BioScience, Marina del Rey, California

Submitted 26 June 2008 ; accepted in final form 23 January 2009

Medial thickening and vascular hypertrophy of resistance arteries can lead to cardiovascular complications associated with diabetes. While previous studies have established a role of Type 1 diabetes in vascular remodeling, we recently extended these observations to Type 2 diabetes and reported increased collagen deposition due to alterations in matrix metalloproteinase expression and activity in mesenteric resistance arteries. These studies also showed that remodeling response was mediated by endothelin-1 (ET-1) via activation of ET_A receptors, whereas blockade of ET_B receptors exacerbated the remodeling. However, the effectiveness of glycemic control strategies in preventing these vascular changes, including activation of the ET system still remained unclear. Also, very little is known about whether and to what extent reorganization of the extracellular matrix (ECM) affects vascular compliance and vasomotor tone. Accordingly, this study assessed structural remodeling of mesenteric microvessels, vascular compliance, and myogenic tone, as well as the role of matrix metalloproteinases (MMP) in mediating these processes. Spontaneously diabetic, non-obese Goto-Kakizaki (GK) rats, a model for Type 2 diabetes, and normoglycemic Wistar rats were used for the studies. A subset of GK rats were administered metformin to achieve euglycemia. Glycemic control normalized the increased media-to-lumen ratios (M/L) and myogenic tone seen in diabetes, as well as normalizing plasma ET-1 levels and mesenteric ET_A receptor expression. There was increased collagen synthesis in diabetes paralleled by decreased collagenase MMP-13 activity, while glycemic control attenuated the process. These findings and our previous study taken together suggest that hyperglycemia-mediated activation of ET-1 and ET_A receptors alter vascular structure and mechanics in Type 2 diabetes.

vascular remodeling; vascular compliance; glycemic control; extracellular matrix; endothelin receptors