VASCULAR HYPERTROPHY IN EXPERIMENTAL DIABETES - ROLE OF ADVANCED GLYCATION END-PRODUCTS

The accelerated formation of advanced glycation end products (AGEs) an d the overexpression of transforming growth factor beta (TGF-beta) hav e both been implicated in the pathogenesis of diabetic microvascular a nd macrovascular complications, Previous studies in our laboratory hav e demonstrated that the vascular changes in diabetes include hypertrop hy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment, Animals were studied at 7 d, 3 wk, and 8 mo after ind uction of diabetes, When compared with control animals, diabetes was a ssociated with an increase in mesenteric vascular weight and an increa se in media wall/lumen area, By Northern analysis, TGF-beta 1 gene exp ression was increased 100-150% (P < 0.01) and alpha 1 (IV) collagen ge ne expression was similarly elevated to 30-110% compared to controls ( P < 0.05), AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with a minoguanidine resulted in significant amelioration of the described pa thological changes including overexpression of TGF-beta 1 and alpha 1 (IV) collagen, These data implicate the formation of AGEs in TGF-beta overexpression and tissue changes which accompany the diabetic state.