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- Title
Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C.
- Authors
Ido, Yasuo; Chang, Katherine C; Lejeune, Wanda S; Bjercke, Robert J; Reiser, Karen M; Williamson, Joseph R; Tilton, Ronald G
- 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 [SUP125]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[SUPG]-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase inhibitor; LY83583, a guanylate cyclase inhibitor; and LY333531, a β-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.
- Subjects
VASCULAR diseases; SERUM albumin; REACTIVE oxygen species
- Publication
Microcirculation, 2001, Vol 8, Issue 4, p251
- ISSN
1073-9688
- Publication type
Article
- DOI
10.1038/sj.mn.7800079