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

Ronald G. Tilton, Takahiko Kawamura, Katherine C. Chang, Yasuo Ido, Robert J. Bjercke, Clifford C. Stephan, Tommy A. Brock, Joseph R. Williamson

Research output: Contribution to journalArticle

168 Scopus citations

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 ~ 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.

Original languageEnglish (US)
Pages (from-to)2192-2202
Number of pages11
JournalJournal of Clinical Investigation
Volume99
Issue number9
DOIs
StatePublished - May 1 1997

Keywords

  • albumin permeation
  • blood flow
  • nitric oxide
  • polyol pathway
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Medicine(all)

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    Tilton, R. G., Kawamura, T., Chang, K. C., Ido, Y., Bjercke, R. J., Stephan, C. C., Brock, T. A., & Williamson, J. R. (1997). Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor. Journal of Clinical Investigation, 99(9), 2192-2202. https://doi.org/10.1172/JCI119392