Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor

J Clin Invest. 1997 May 1;99(9):2192-202. doi: 10.1172/JCI119392.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcimycin / pharmacology
  • Cell Membrane Permeability
  • Endothelial Growth Factors / antagonists & inhibitors
  • Endothelial Growth Factors / metabolism
  • Endothelial Growth Factors / physiology*
  • Female
  • Glucose / metabolism*
  • Guanidines / pharmacology
  • Humans
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / metabolism
  • Lymphokines / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Nitroprusside / pharmacology
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Regional Blood Flow*
  • Serum Albumin / metabolism*
  • Skin / blood supply*
  • Sorbitol / metabolism
  • Superoxides / metabolism
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • omega-N-Methylarginine / pharmacology

Substances

  • Endothelial Growth Factors
  • Guanidines
  • Lymphokines
  • Recombinant Proteins
  • Serum Albumin
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Superoxides
  • Nitroprusside
  • omega-N-Methylarginine
  • Calcimycin
  • Sorbitol
  • Glucose
  • pimagedine