Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.
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.
Tilton
R G
RG
Department of Cell Biology, Texas Biotechnology Corporation, Houston 77030, USA. rtilton@tbc.com
Kawamura
T
T
Chang
K C
KC
Ido
Y
Y
Bjercke
R J
RJ
Stephan
C C
CC
Brock
T A
TA
Williamson
J R
JR
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002463:Cell Membrane Permeability; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009599:Nitroprusside / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012039:Regional Blood Flow; D012709:Serum Albumin / Q000378:metabolism*; D012867:Skin / Q000098:blood supply*; D013012:Sorbitol / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016228:Endothelial Growth Factors; D006146:Guanidines; D008222:Lymphokines; D011994:Recombinant Proteins; D012709:Serum Albumin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013481:Superoxides; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D000001:Calcimycin; D013012:Sorbitol; D005947:Glucose; C004479:pimagedine