| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
It has been shown that patients and experimental animal models with diabetes have a lesser ability to develop collateral blood vessels in arterial occlusion. However, the molecular and cellular mechanism underlying impaired arteriogenesis in diabetes is not known. In the present study, we examined the role of advanced glycation endproducts, AGE, and its receptor, RAGE, in diabetes-associated impaired smooth muscle cell (SMC) function and arteriogenesis. On glycolaldehyde-induced glycated form of type 1 fibrillar collagen (AGE-collagen), basal or PDGF-stimulated SMC migration was markedly decreased as compared with SMC cultured on native collagen. Analyses of candidate receptors for type 1 collagen revealed that expression of α2 integrins is suppressed, while levels of αv integrins are upregulated in SMC cultured on AGE-collagen. Culture on AGE collagen suppresses secretion and mRNA expression of vascular endothelial growth factor (VEGF), but enhances mRNA expression of thrombospondin-1, an inhibitor of angiogenesis. To examine arteriogenesis in vivo, we subcutaneously implanted VEGF-containing matrigel to streptozotocin-induced diabetic or control mice. In diabetic mice, numbers of α-actin positive SMC or pericytes migrated into matrigel was decreased by 25% as compared with control mice. Similarly CD31-positive endothelial cells infiltrated less in diabetic mice. Importantly, impaired migration of both SMC and endothelial cells into matrigel in diabetes was completely restored in RAGE-deficient mice. Thus, AGE-RAGE system appears to play fundamental role in impaired arteriogenesis in diabetes.
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