Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C.
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.
Ido
Y
Y
Diabetes Metabolism Unit, Boston University, Boston, MA, USA.
Chang
K C
KC
Lejeune
W S
WS
Bjercke
R J
RJ
Reiser
K M
KM
Williamson
J R
JR
Tilton
R G
RG
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
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