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 f or vascular endothelial growth factor (VEGF) in mediating vascular dys function induced by increased glucose flux via the sorbitol pathway, S kin 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 a nd absence of neutralizing VEGF antibodies, Albumin permeation and blo od flow were increased two- to three-fold by 30 mM glucose and 1 mM so rbitol; these increases were prevented by coadministration of neutrali zing VEGF antibodies, Blood flow and albumin permeation were increased similar to 2.5-fold 1 h after topical application of recombinant huma n VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N-G-monomethyl L-arginine). Topical ap plication of a superoxide generating system increased albumin permeati on and blood flow and these changes were markedly attenuated by VEGF a ntibody and NOS inhibitors, Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked e ffects 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 me diating vascular dysfunction induced by ''hypoxia-like'' cytosolic met abolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway.