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Diabetes 54:2638-2644, 2005
© 2005 by the American Diabetes Association, Inc.

Type 2 Diabetes Causes Remodeling of Cerebrovasculature via Differential Regulation of Matrix Metalloproteinases and Collagen Synthesis

Role of Endothelin-1

Alex K. Harris1, Jim R. Hutchinson1, Kamakshi Sachidanandam1, Maribeth H. Johnson2, Anne M. Dorrance3, David W. Stepp4, Susan C. Fagan1, and Adviye Ergul1,4

1 Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia
2 Department of Biostatistics, Medical College of Georgia, Augusta, Georgia
3 Department of Physiology, Medical College of Georgia, Augusta, Georgia
4 Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

The risk of cerebrovascular disease is four- to sixfold higher in patients with diabetes. Vascular remodeling, characterized by extracellular matrix deposition and an increased media-to-lumen ratio, occurs in diabetes and contributes to the development of complications. However, diabetes-induced changes in the cerebrovascular structure remain unknown. Endothelin-1 (ET-1), a potent vasoconstrictor with profibrotic properties, is chronically elevated in diabetes. To determine diabetes-mediated changes in the cerebrovasculature and the role of ET-1 in this process, type 2 diabetic Goto-Kakizaki (GK) rats were administered an ETA receptor antagonist for 4 weeks. Middle cerebral arteries were harvested and studies were performed to determine vascular structure. Tissue and plasma ET-1 levels were increased in GK rats compared with controls. Significant medial hypertrophy and collagen deposition resulted in an increased wall-to-lumen ratio in diabetic rats that was reduced by ETA receptor antagonism. Vascular matrix metalloproteinase (MMP)-2 activity was higher, but MMP-1 levels were significantly reduced in GK rats, and MMP levels were restored to control levels by ETA receptor antagonism. We conclude that ET-1 promotes cerebrovascular remodeling in type 2 diabetes through differential regulation of MMPs. Augmented cerebrovascular remodeling may contribute to an increased risk of stroke in diabetes, and ETA receptor antagonism may offer a novel therapeutic target.

Address correspondence and reprint requests to Adviye Ergul, MD, PhD, Medical College of Georgia, Clinical Pharmacy CJ-1020, Augusta, GA 30912. E-mail: aergul{at}mail.mcg.edu

Abbreviations: ET-1, endothelin-1; MMP, matrix metalloproteinase; TIMP-2, tissue inhibitor of metalloproteinase-2


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