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Vascular Dysfunction Induced by AGE is Mediated by VEGF via Mechanisms Involving Reactive Oxygen Species, Guanylate Cyclase, and Protein Kinase C
Author(s) -
IDO YASUO,
CHANG KATHERINE C.,
LEJEUNE WANDA S.,
BJERCKE ROBERT J.,
REISER KAREN M.,
WILLIAMSON JOSEPH R.,
TILTON RONALD G.
Publication year - 2001
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1111/j.1549-8719.2001.tb00174.x
Subject(s) - chemistry , nitric oxide , glycation , protein kinase c , nitric oxide synthase , protein kinase a , albumin , medicine , endocrinology , vascular permeability , vascular endothelial growth factor , biochemistry , soluble guanylyl cyclase , cgmp dependent protein kinase , reactive oxygen species , pharmacology , kinase , biology , receptor , mitogen activated protein kinase kinase , organic chemistry , guanylate cyclase , vegf receptors
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 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.