Figure 2: The FGF/VEGF system and its alterations in diabetes: the effects of CaD. In diabetic patients VEGF and its receptors are overexpressed. Circulating growth factors requires two binding sites in order to elicit a cellular response: (1) to heparan sulfate domains on extracellular proteoglycans and (2) to its specific membrane-bound receptor. The heparan sulfate domains provide a gradient for growth factors and allow coordinated binding to their receptors where intracellular pathways are activated which lead to endothelial dysfunction, albuminuria, and angiogenesis. The heparin binding sites are regulated physiologically by heparanases and sulfatases. CaD binds specifically to the negatively charged domain of growth factors thereby interfering with their binding to their receptors and thus reducing endothelial cell dysfunction, albuminuria, and angiogenesis under diabetic conditions. While VEGF antibodies completely block the effects of VEGF on the intracellular signaling pathways and thereby also blocking the VEGF-induced signals which are necessary for endothelial cell survival, interference with the heparin sulfate binding sites reduces the binding of VEGF and FGF to its coreceptor and therefore reduces its effects on endothelial cells but does not abolish the effect of VEGF on its specific membrane-bound receptor. VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor.