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 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. Diabetes 55: [2245][2246][2247][2248][2249][2250][2251][2252][2253][2254][2255] 2006

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…Blockade of RAGE by administration of genetically engineered sRAGE successfully prevented the development of micro- 132,133 and macrovascular complications in diabetes [134][135][136] . We have also shown that adenoviral overexpression of esRAGE successfully restored the impaired angiogenic response in diabetic mice 101 . Sakaguchi et al found that administration of sRAGE markedly suppressed neointimal formation following arterial injury in non-diabetic mice 137 .…”

“…esRAGE was found to be capable of neutralizing the effects of AGEs on endothelial cells in culture 12 . Adenoviral overexpression of esRAGE in vivo in mice reverses diabetic impairment of vascular dysfunction 101 . Thus, the decoy function of esRAGE may exhibit a feedback mechanism by which esRAGE prevents the activation of RAGE signaling.…”

TUNEL-positive cells in the surgical border of an amputation due to infected diabetic foot

“…However, diabetic patients have defects in the process of cicatrization and in the resolution of injury due to cellular dysfunction and inadequate production of proteases, cytokines and growth factors. The activation of receptors for advanced glycation end products may decrease angiogenesis and increase apoptosis (43). By contrast, the inflammatory reaction in diabetic lesions with poor cicatrization appears to slow recovery by generating an intense proteolytic response, which is mediated by elastase and neutrophils, TNF and IL-1.…”

Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

“…It has been shown that RAGE is associated with plaque apoptosis and diabetic vascular responses 46,47) . In this study, we found that both temocaprilat and olmesartan prevented AGE-induced SMC apoptosis, probably due to the attenuation of RAGE/NADPH oxidase-dependent pathways.…”