title: Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice.
abstract: The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic 'swings'. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named 'V') and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named 'S') for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.
authors: Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy. f.biscetti@gmail.com
authors: Federico
authors: F
authors: Biscetti
authors: Dario
authors: D
authors: Pitocco
authors: Giuseppe
authors: G
authors: Straface
authors: Francesco
authors: F
authors: Zaccardi
authors: Raimondo
authors: R
authors: de Cristofaro
authors: Paola
authors: P
authors: Rizzo
authors: Stefano
authors: S
authors: Lancellotti
authors: Vincenzo
authors: V
authors: Arena
authors: Egidio
authors: E
authors: Stigliano
authors: Tittania
authors: T
authors: Musella
authors: Giovanni
authors: G
authors: Ghirlanda
authors: Andrea
authors: A
authors: Flex
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000097:blood / Q000503:physiopathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D001786:Blood Glucose; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt