Role for heparin-binding growth factors in glucose-induced vascular dysfunction.

Abstract

Vascular hyperpermeability and excessive neovascularization are hallmarks 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 reported previously, using skin chambers mounted on backs of SD rats, that neutralizing antibodies directed against VEGF blocked vascular permeability and blood flow changes induced by elevated tissue glucose and sorbitol levels in a dosage-dependent manner. We report in this study, using 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 sorbitol-induced vascular permeability and blood flow increases. In addition, we show that 1) TBC1635, a novel heparin-binding growth factor antagonist, blocks the vascular hyperpermeability and blood flow increases induced by elevated tissue levels of glucose and sorbitol and by topical application of VEGF and FGF-2 to granulation tissue in skin chambers, and 2) suramin, a commercially available growth factor antagonist, blocks glucose-induced vascular dysfunction. These results suggest an early role for heparin-binding growth factors in the vascular dysfunction caused by excessive glucose metabolism, possibly via the sorbitol pathway.

The effect of elevated extracellular glucose on adherens junction proteins in cultured rat heart endothelial cells

“…The main change in vascular cells has been identified to be those hyperglycemiainduced biochemical changes that are significant in causing vascular dysfunctions (Ruderman et al, 1992;Kim et al, 1994;King et al, 1994). Several lines of evidence suggest that increased vascular permeability should be one of the characteristic systemic vascular dysfunctions (Stephan et al, 1998;Fujita, 1999;Brausewetter et al, 2001). However, the integrity of the endothelium plays an essential role in controlling vascular permeability.…”

“…Furthermore, the opening of the intercellular junction to macromolecules is thought to result in edema formation. It has been reported that high-glucose stimulates the formation of intercellular gaps and induces an increase of permeability in the confluent endothelium (Stephan et al, 1998;Fujita, 1999;Brausewetter et al, 2001). A number of in vitro studies have demonstrated that cell shape change or contraction involves a complex interaction between contractile elements and adhesive molecules (Moy et al, 1996;Yuan et al, 1998).…”

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney

“…However, an increase in plasma FGF2 levels is expected in the pathophysiological condition of endothelial injury. Regarding diabetes, Stephan et al 31 showed that FGF2 is closely involved in glucose-induced vascular dysfunction. Hamed et al 32 also reported a marked increase in serum levels of FGF2 in T2DM compared with those of healthy controls.…”

Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts

“…Particularly, important roles for transforming growth factor-␤ (TGF-␤) (32) and connective tissue growth factor (43) have been described in diabetic nephropathy (DN). In addition, angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor (FGF-2) were reported to contribute to the glucose-induced vascular dysfunction (34,48). Nevertheless, the importance of their nonangiogenic effects in kidney remains unclear.…”