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Receptor for Advanced Glycation End Products Is Involved in Impaired Angiogenic Response in Diabetes

¹ Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
² Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
³ Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
⁴ Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

Address correspondence and reprint requests to Hidenori Koyama, MD, PhD, Department of Metabolism, Endocrinology and Molecular Medicine, (Second Department of Internal Medicine), Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: hidekoyama{at}med.osaka-cu.ac.jp

Abbreviations: SM actin, smooth muscle actin; Ad-esRAGE, pAdHM15-esRAGE; AGE, advanced glycation end product; CML, N-carboxymethyllysine; esRAGE, endogenous secretory RAGE; MMP, matrix metalloproteinase; NF-B, nuclear factor-B; PCNA, proliferating cell nuclear antigen; RAGE, receptor for AGE; STZ, streptozotocin; TSP, thrombospondin; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; VEGF, vascular endothelial growth factor

Angiogenic response is impaired in diabetes. Here, we examined the involvement of receptor for advanced glycation end products (RAGE) in diabetes-related impairment of angiogenesis in vivo. Angiogenesis was determined in reconstituted basement membrane protein (matrigel) plugs containing vascular endothelial growth factor (VEGF) implanted into nondiabetic or insulin-deficient diabetic wild-type or RAGE^–/– mice. The total, endothelial, and smooth muscle (or pericytes) cells in the matrigel were significantly decreased in diabetes, with the regulation dependent on RAGE. In the matrigel, proangiogenic VEGF expression was decreased, while antiangiogenic thrombospondin-1 was upregulated in diabetic mice, regardless of the presence of RAGE. In wild-type mice, proliferating cell nuclear antigen (PCNA)-positive cells in the matrigel were significantly less in diabetic than in nondiabetic mice, while the numbers of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were significantly higher. This alteration in PCNA- and TUNEL-positive cells in diabetes was not observed in RAGE^–/– mice. Similarly, the percentage of nuclear factor B–activated cells is enhanced in diabetes, with the regulation dependent on the presence of RAGE. Importantly, adenovirus-mediated overexpression of endogenous secretory RAGE, a decoy receptor for RAGE, restores diabetes-associated impairment of angiogenic response in vivo. Thus, RAGE appears to be involved in impairment of angiogenesis in diabetes, and blockade of RAGE might be a potential therapeutic target.

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