Ager Deletion Enhances Ischemic Muscle Inflammation, Angiogenesis, and Blood Flow Recovery in Diabetic Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 37; no. 8; pp. 1536 - 1547
• Main Authors: López-Díez, Raquel, Shen, Xiaoping, Daffu, Gurdip, Khursheed, Md, Hu, Jiyuan, Song, Fei, Rosario, Rosa, Xu, Yunlu, Li, Qing, Xi, Xiangmei, Zou, Yu Shan, Li, Huilin, Schmidt, Ann Marie, Yan, Shi Fang
• Format: Journal Article
• Language: English
• Published: United States 01.08.2017
• Subjects: Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; Antigens, Ly - metabolism; Blood Flow Velocity; Blood Glucose - metabolism; Cell Communication; Cells, Cultured; Cellular Microenvironment; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - physiopathology; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Endothelial Cells - metabolism; Gene Deletion; Gene Expression Regulation; Genetic Predisposition to Disease; Glycation End Products, Advanced - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - physiopathology; Ischemia - genetics; Ischemia - metabolism; Ischemia - physiopathology; Macrophages - metabolism; Mice, Knockout; Mice, Transgenic; Monocytes - metabolism; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Neovascularization, Physiologic; Peripheral Arterial Disease - genetics; Peripheral Arterial Disease - metabolism; Peripheral Arterial Disease - physiopathology; Phenotype; Receptor for Advanced Glycation End Products - deficiency; Receptor for Advanced Glycation End Products - genetics; Recovery of Function; Regional Blood Flow; Signal Transduction; Streptozocin; Time Factors; monocytes; diabetes mellitus; inflammation; receptor for AGE (RAGE); angiogenesis; peripheral vascular disease
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.117.309714

Diabetic subjects are at higher risk of ischemic peripheral vascular disease. We tested the hypothesis that advanced glycation end products (AGEs) and their receptor (RAGE) block angiogenesis and blood flow recovery after hindlimb ischemia induced by femoral artery ligation through modulation of immune/inflammatory mechanisms. Wild-type mice rendered diabetic with streptozotocin and subjected to unilateral femoral artery ligation displayed increased accumulation and expression of AGEs and RAGE in ischemic muscle. In diabetic wild-type mice, femoral artery ligation attenuated angiogenesis and impaired blood flow recovery, in parallel with reduced macrophage content in ischemic muscle and suppression of early inflammatory gene expression, including (chemokine [C-C motif] ligand-2) and (early growth response gene-1) versus nondiabetic mice. Deletion of (gene encoding RAGE) or transgenic expression of (reduces AGEs) restored adaptive inflammation, angiogenesis, and blood flow recovery in diabetic mice. In diabetes mellitus, deletion of increased circulating Ly6C monocytes and augmented macrophage infiltration into ischemic muscle tissue after femoral artery ligation. In vitro, macrophages grown in high glucose display inflammation that is skewed to expression of tissue damage versus tissue repair gene expression. Further, macrophages grown in high versus low glucose demonstrate blunted macrophage-endothelial cell interactions. In both settings, these adverse effects of high glucose were reversed by deletion in macrophages. These findings indicate that RAGE attenuates adaptive inflammation in hindlimb ischemia; underscore microenvironment-specific functions for RAGE in inflammation in tissue repair versus damage; and illustrate that AGE/RAGE antagonism may fill a critical gap in diabetic peripheral vascular disease.