title: Receptor for advanced glycation end products is involved in impaired angiogenic response in diabetes.
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 kappaB-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.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Osaka 545-8585, Japan.
authors.forename: Takuhito
authors.initials: T
authors.lastname: Shoji
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Akane
authors.initials: A
authors.lastname: Kizu
authors.forename: Kohka
authors.initials: K
authors.lastname: Motoyama
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Mori
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shioi
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimogaito
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D042683:Angiopoietin-1 / Q000032:analysis; D042702:Angiopoietin-2 / Q000032:analysis; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D002455:Cell Division; D003094:Collagen; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004338:Drug Combinations; D004343:Drug Implants; D042783:Endothelial Cells; D015870:Gene Expression; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000097:blood; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D016328:NF-kappa B / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011509:Proteoglycans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019700:Thrombospondin 1 / Q000032:analysis; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000032:analysis
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D004338:Drug Combinations; D004343:Drug Implants; D017127:Glycation End Products, Advanced; D007797:Laminin; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D011509:Proteoglycans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9