A survey of defined species of cell surface and extracellular matrix heparan sulfate proteoglycans (HSPG) was performed in a search for cellular proteoglycans that can promote bFGF receptor binding and biological activity. Of the various affinity-purified HSPGs tested, perlecan, the large basement membrane HSPG, is found to induce high affinity binding of bFGF both to cells deficient in HS and to soluble FGF receptors. Heparin-dependent mitogenic activity of bFGF is strongly augmented by perlecan. Monoclonal antibodies to perlecan extract the receptor binding promoting activity from active HSPG preparations. In a rabbit ear model for in vivo angiogenesis, perlecan is a potent inducer of bFGF-mediated neovascularization. These results identify perlecan as a major candidate for a bFGF low affinity, accessory receptor and an angiogenic modulator.

Fibroblast growth factors (FGFs) are potent growth and angiogenic factors abundant in normal and malignantly transformed cells (Folkman and Klagsbrun, 1987). Basic FGF (bFGF) binds avidly to the glycosaminoglycan heparin and to heparan sulfates (HSs) found on cells and in the extracellular matrix (ECM). bFGF has been identified as a complex with HS in subendothelial ECM (Vlodavsky et al., 1987) and in basement membranes of diverse tissues and blood vessels (Folkman et al., 1988). Recent studies on the mode of action of bFGF identified a novel role for heparin-like molecules in the formation of distinct bFGF-heparin complexes that are essential for binding of bFGF to its cognate receptor. The crucial role of cellular WS was revealed by the finding that high affinity receptor binding of bFGF is abrogated in Chinese hamster ovary (CHO) mutant cell lines defective in their metabolism of glycosaminoglycans (Yayon et al., 1991) and in sulfatedepleted myoblasts (Rapraeger et al., 1991). Subsequent