title: Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C.
abstract: OBJECTIVE
  These experiments were designed to elucidate mechanisms mediating vascular dysfunction induced by advanced glycation end products (AGEs).
  
  
  METHODS
  Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 week later, granulation tissue that formed in the bottom of the chamber was exposed twice daily for 7 days to glycated rat serum albumin in the presence and absence of inhibitors of reactive oxygen intermediates, nitric oxide synthase and guanylate cyclase, protein kinase C (PKC), and a neutralizing vascular endothelial growth factor (VEGF) antibody. Vascular (125)I-albumin clearance and blood flow were quantified by use of a double isotope-dilution technique and radiolabeled microspheres, respectively.
  
  
  RESULTS
  Albumin permeation and blood flow were increased dose-dependently to a maximum of 2 to 3 times controls by increasing the extent of glucose modification, the concentration, or the duration of exposure to glycated albumin. These increases were significantly attenuated by probucol and superoxide dismutase; N(G)-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase inhibitor; LY83583, a guanylate cyclase inhibitor; and LY333531, a beta-isoform-selective protein kinase C inhibitor. A neutralizing VEGF monoclonal antibody also markedly attenuated the permeability and blood flow increases induced by glycated albumin.
  
  
  CONCLUSIONS
  These observations indicate potentially important roles for oxygen free-radicals and nitric oxide in mediating permeability and blood flow changes induced by glycated proteins via mechanisms involving increased protein kinase C activity and VEGF production. Striking similarities in the mechanism by which hyperglycemia and glycated proteins induce vascular dysfunction suggest that a common pathway mediates effects of these different metabolic imbalances on vascular dysfunction.
authors.affiliation: Diabetes Metabolism Unit, Boston University, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ido
authors.forename: K C
authors.initials: KC
authors.lastname: Chang
authors.forename: W S
authors.initials: WS
authors.lastname: Lejeune
authors.forename: R J
authors.initials: RJ
authors.lastname: Bjercke
authors.forename: K M
authors.initials: KM
authors.lastname: Reiser
authors.forename: J R
authors.initials: JR
authors.lastname: Williamson
authors.forename: R G
authors.initials: RG
authors.lastname: Tilton
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology* / Q000502:physiology; D006097:Granulation Tissue / Q000098:blood supply; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D008222:Lymphokines / Q000494:pharmacology*; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism; D014652:Vascular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000093423:Glycated Serum Albumin
chemical_list: D000975:Antioxidants; D016228:Endothelial Growth Factors; D017127:Glycation End Products, Advanced; D008222:Lymphokines; D017382:Reactive Oxygen Species; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011493:Protein Kinase C; D006162:Guanylate Cyclase; D000093423:Glycated Serum Albumin