Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C

Yasuo Ido, Katherine C. Chang, Wanda S. Lejeune, Robert J. Bjercke, Karen M. Reiser, Joseph R. Williamson, Ronald Tilton

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Objective: These experiments were designed to elucidate mechanisms mediating vascular dysfunction induced by advanced glycation end products (ACEs). 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 (VECF) antibody. Vascular 125l-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; NG-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. Microcirculation (2001) 8, 251-263.

Original languageEnglish (US)
Pages (from-to)251-263
Number of pages13
JournalMicrocirculation
Volume8
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

Guanylate Kinases
Guanylate Cyclase
Protein Kinase C
Vascular Endothelial Growth Factor A
Blood Vessels
Reactive Oxygen Species
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase
ruboxistaurin
Albumins
Permeability
6-anilino-5,8-quinolinedione
Probucol
Indicator Dilution Techniques
Advanced Glycosylation End Products
Granulation Tissue
Protein C Inhibitor
Protein Kinase Inhibitors
Microcirculation
Microspheres

Keywords

  • Advanced glycation end products
  • Albumin permeation
  • Blood flow
  • Diabetes
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Genetics
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. / Ido, Yasuo; Chang, Katherine C.; Lejeune, Wanda S.; Bjercke, Robert J.; Reiser, Karen M.; Williamson, Joseph R.; Tilton, Ronald.

In: Microcirculation, Vol. 8, No. 4, 2001, p. 251-263.

Research output: Contribution to journalArticle

Ido, Yasuo ; Chang, Katherine C. ; Lejeune, Wanda S. ; Bjercke, Robert J. ; Reiser, Karen M. ; Williamson, Joseph R. ; Tilton, Ronald. / Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. In: Microcirculation. 2001 ; Vol. 8, No. 4. pp. 251-263.
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T1 - Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C

AU - Ido, Yasuo

AU - Chang, Katherine C.

AU - Lejeune, Wanda S.

AU - Bjercke, Robert J.

AU - Reiser, Karen M.

AU - Williamson, Joseph R.

AU - Tilton, Ronald

PY - 2001

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N2 - Objective: These experiments were designed to elucidate mechanisms mediating vascular dysfunction induced by advanced glycation end products (ACEs). 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 (VECF) antibody. Vascular 125l-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; NG-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. Microcirculation (2001) 8, 251-263.

AB - Objective: These experiments were designed to elucidate mechanisms mediating vascular dysfunction induced by advanced glycation end products (ACEs). 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 (VECF) antibody. Vascular 125l-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; NG-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. Microcirculation (2001) 8, 251-263.

KW - Advanced glycation end products

KW - Albumin permeation

KW - Blood flow

KW - Diabetes

KW - Vascular endothelial growth factor

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