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 s everal physiological and pathological processes, including wound repai r, embryonic development; and tumor growth. In vitro, basic fibroblast growth factor induces an ''angiogenic phenotype'' in endothelial cell s, which includes chemotaxis, mitogenesis, protease production, beta-i ntegrin expression, and tube formation in three-dimensional gels. It a cts by binding to specific tryosine kinase receptors and to cell-assoc iated heparan sulfate proteoglycans. The physiological significance of the interaction with cell-associated and soluble heparan sulfate prot eoglycans is manyfold. Heparan sulfate proteoglycans protect basic fib roblast growth factor from inactivation in the extracellular environme nt 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 interacti on with tyrosine kinase receptors. Finally, they affect the internaliz ation and the intracellular fate of basic fibroblast growth factor, su ggesting that growth factor slash proteoglycan complexes are involved in intracellular delivery. The bioavailability and the biological acti vity of basic fibroblast growth factor on endothelial cells strictly d epend 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 glyco saminoglycans to bind to and to influence the biological activity of b asic fibroblast growth factor depends on size, degree of sulfation, an d disaccharide composition, In the present paper we discuss the physio logical significance and the biochemical bases of the interaction of t he growth factor with heparan sulfate proteoglycans and exogenous glyc osaminoglycans with a view to the possible therapeutic use of heparin- related oligosaccharides as basic fibroblast growth factor agonists or antagonists in angiogenesis-dependent diseases.