Interaction of angiogenic basic fibroblast growth factor with endothelial cell heparan sulfate proteoglycans. Biological implications in neovascularization

Basic Fibroblast Growth Factor is an angiogenic molecule involved in several physiological and pathological processes, including wound repair, embryonic development, and tumor growth. In vitro, basic Fibroblast Growth Factor induces an "angiogenic phenotype" in endothelial cells, which includes chemotaxis, mitogenesis, Protease production, beta-integrin expression, and tube formation in three-dimensional gels. It acts by binding to specific tyrosine kinase receptors and to cell-associated heparan sulfate proteoglycans. The physiological significance of the interaction with cell-associated and soluble heparan sulfate proteoglycans is manyfold. Heparan sulfate proteoglycans protect basic Fibroblast Growth Factor from inactivation in the extracellular environment and modulate its bioavailability. At the cell surface, soluble and cell-associated heparan sulfate proteoglycans may play different roles in modulating the dimerization of the growth factor and its interaction with tyrosine kinase receptors. Finally, they affect the internalization and the intracellular fate of basic Fibroblast Growth Factor, suggesting that growth factor slash proteoglycan complexes are involved in intracellular delivery. The bioavailability and the biological activity of basic Fibroblast Growth Factor on endothelial cells strictly depend on the glycosaminoglycan milieu of the extracellular environment. Hence the angiogenic activity of the growth factor in vivo might be modulated by using exogenous glycosaminoglycans. The capacity of glycosaminoglycans to bind to and to influence the biological activity of basic Fibroblast Growth Factor depends on size, degree of sulfation, and disaccharide composition. In the present paper we discuss the physiological significance and the biochemical bases of the interaction of the growth factor with heparan sulfate proteoglycans and exogenous glycosaminoglycans with a view to the possible therapeutic use of heparin-related oligosaccharides as basic Fibroblast Growth Factor agonists or antagonists in angiogenesis-dependent diseases.