Receptor for Advanced Glycation End Products Is Involved in Impaired Angiogenic Response in Diabetes
Author:
Shoji Takuhito1, Koyama Hidenori1, Morioka Tomoaki1, Tanaka Shinji1, Kizu Akane1, Motoyama Kohka1, Mori Katsuhito1, Fukumoto Shinya1, Shioi Atsushi2, Shimogaito Noriko3, Takeuchi Masayoshi3, Yamamoto Yasuhiko4, Yonekura Hideto4, Yamamoto Hiroshi4, Nishizawa Yoshiki1
Affiliation:
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
Abstract
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 κB–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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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