LOW-SULFATED OLIGOSACCHARIDES DERIVED FROM HEPARAN-SULFATE INHIBIT NORMAL ANGIOGENESIS

Heparin, with or without the addition of an adrenocorticosteroid, can inhibit normal angiogenesis in the chick embryo chorioallantoic membrane. Low- or non-sulphated heparin fragments also have anti-angiogenic effect. Attempts to define a saccharide structure responsible for the antiangiogenic effect implicated a -[GlcA beta 1,4-GlcNAc alpha 1,4](n)-sequence. This structure represents the product of the initial polymerization reaction in heparin/heparan sulphate biosynthesis. It persists in the non-sulphated regions of heparan sulphate and also occurs in the Escherichia coli K5 capsular polysaccharide. The K5 polysaccharide, fragments thereof down to octasaccharide size and analogous N-acetylated fragments of heparan sulphate, all showed anti-angiogenic activity. Hyaluronan, however, with the isomeric -[GlcA beta 1,3-GlcNAc beta 1,4](n)-structure was inactive. The antiangiogenic activity of -[GlcA beta 1,4-GlcNAc alpha 1,4](n)-containing saccharides was potentiated by the presence of L-iduronic acid and one or two O-sulphate groups in the non-reducing-terminal disaccharide unit. The anti-angiogenic effect of these non- or low-sulphated saccharides was unaffected by the addition of hydrocortisone. Endothelial cell surface-bound heparan sulphate proteoglycans may represent a pool of precursors of anti-angiogenic oligosaccharides which may be of primary importance in the regulation of angiogenesis.