Receptor for advanced glycation end products is involved in impaired angiogenic response in diabetes.
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.
Shoji
Takuhito
T
Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Osaka 545-8585, Japan.
Koyama
Hidenori
H
Morioka
Tomoaki
T
Tanaka
Shinji
S
Kizu
Akane
A
Motoyama
Kohka
K
Mori
Katsuhito
K
Fukumoto
Shinya
S
Shioi
Atsushi
A
Shimogaito
Noriko
N
Takeuchi
Masayoshi
M
Yamamoto
Yasuhiko
Y
Yonekura
Hideto
H
Yamamoto
Hiroshi
H
Nishizawa
Yoshiki
Y
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
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