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Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 1997 May 01; Vol. 99 (9), pp. 2192-202. - Publication Year :
- 1997
-
Abstract
- The purpose of these experiments was to investigate a potential role for vascular endothelial growth factor (VEGF) in mediating vascular dysfunction induced by increased glucose flux via the sorbitol pathway. Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 wk later, granulation tissue in the chamber was exposed twice daily for 7 d to 5 mM glucose, 30 mM glucose, or 1 mM sorbitol in the presence and absence of neutralizing VEGF antibodies. Albumin permeation and blood flow were increased two- to three-fold by 30 mM glucose and 1 mM sorbitol; these increases were prevented by coadministration of neutralizing VEGF antibodies. Blood flow and albumin permeation were increased approximately 2.5-fold 1 h after topical application of recombinant human VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N(G)-monomethyl L-arginine). Topical application of a superoxide generating system increased albumin permeation and blood flow and these changes were markedly attenuated by VEGF antibody and NOS inhibitors. Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked effects of glucose, sorbitol, and VEGF on vascular dysfunction and the ionophore effect was prevented by coadministration of aminoguanidine. These observations suggest a potentially important role for VEGF in mediating vascular dysfunction induced by "hypoxia-like" cytosolic metabolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway.
- Subjects :
- Animals
Calcimycin pharmacology
Cell Membrane Permeability
Endothelial Growth Factors antagonists & inhibitors
Endothelial Growth Factors metabolism
Female
Guanidines pharmacology
Humans
Lymphokines antagonists & inhibitors
Lymphokines metabolism
Male
Mice
Mice, Inbred BALB C
Nitroprusside pharmacology
Rabbits
Rats
Rats, Sprague-Dawley
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins metabolism
Sorbitol metabolism
Superoxides metabolism
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
omega-N-Methylarginine pharmacology
Endothelial Growth Factors physiology
Glucose metabolism
Lymphokines physiology
Regional Blood Flow
Serum Albumin metabolism
Skin blood supply
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 99
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 9151791
- Full Text :
- https://doi.org/10.1172/JCI119392