ROLE FOR HEPARIN-BINDING GROWTH-FACTORS IN GLUCOSE-INDUCED VASCULAR DYSFUNCTION

Vascular hyperpermeability and excessive neovascularization are hallma rks of early and late vascular endothelial cell dysfunction induced by diabetes. Vascular endothelial growth factor (VEGF) appears to be an important mediator for these early and late vascular changes. We repor ted previously, using skin chambers mounted on backs of SD rats, that neutralizing antibodies directed against VEGF blocked vascular permeab ility and blood flow changes induced by elevated tissue glucose and so rbitol levels in a dosage-dependent manner. We report in this study, u sing the same skin chamber model and neutralizing antibodies directed against basic fibroblast growth factor (FGF-2), that another member of the heparin-binding growth factor family also mediates glucose- and s orbitol-induced vascular permeability and blood flow increases. In add ition, we show that 1) TBC1635, a novel heparin-binding growth factor antagonist, blocks the vascular hyperpermeability and blood flow incre ases induced by elevated tissue levels of glucose and sorbitol and by topical application of VEGF and FGF-2 to granulation tissue in skin ch ambers, and 2) suramin, a commercially available growth factor antagon ist, blocks glucose-induced vascular dysfunction. These results sugges t an early role for heparin-binding growth factors in the vascular dys function caused by excessive glucose metabolism, possibly via the sorb itol pathway.