MITOGENIC ACTIVITY OF ACIDIC FIBROBLAST GROWTH-FACTOR IS ENHANCED BY HIGHLY SULFATED OLIGOSACCHARIDES DERIVED FROM HEPARIN AND HEPARAN-SULFATE

The mitogenic activity of acidic fibroblast growth factor (aFGF) is po tentiated by the highly sulfated hexasaccharide [IdoUA,2S-GlcNS,6S]2-[ GlcUA-GlcNS,6S] the structural repetitive unit of lung heparin chains. On a mass basis, the effect of both heparin and oligosaccharide are e quivalent whereas on a molar basis, heparin, which contains about seve n hexasaccharide repeats, is more efficient. On the other hand, a pent asulfated tetrasaccharide or di- and tri-sulfated disaccharides are mu ch less effective in potentiating aFGF activity than the hexasaccharid e. If the growth factor is pre-incubated with the hexasaccharide at pH 7.2 and then exposed to pH 3.5 the 306/345 nm fluorescence ratio is s imilar to that of native aFGF indicating that the oligosaccharide stab ilizes a native conformation of the protein. Heparan sulfates extracte d from various mammalian tissues were also able to potentiate aFGF mit ogenic activity. On a mass basis they were in general less efficient t han heparin; however, heparan sulfate prepared from medium conditioned by 3T3 fibroblasts is more efficient than heparin both on a mass and molar basis. A highly sulfated oligosaccharide isolated after digestio n of pancreas heparan sulfate with heparitinase I is more active than the intact molecule, reaching a potentiating effect equivalent to that of lung heparin, whereas an N-acetylated oligosaccharide isolated aft er nitrous acid degradation is inactive. These data suggest that the m itogenic activity of aFGF is primarily potentiated by interacting with highly sulfated regions of heparan sulfates chains.