Heparin, with or without the addition of an adrenocorticosteroid, can
inhibit normal angiogenesis in the chick embryo chorioallantoic membra
ne. 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 polym
erization reaction in heparin/heparan sulphate biosynthesis. It persis
ts in the non-sulphated regions of heparan sulphate and also occurs in
the Escherichia coli K5 capsular polysaccharide. The K5 polysaccharid
e, fragments thereof down to octasaccharide size and analogous N-acety
lated fragments of heparan sulphate, all showed anti-angiogenic activi
ty. 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 effe
ct of these non- or low-sulphated saccharides was unaffected by the ad
dition of hydrocortisone. Endothelial cell surface-bound heparan sulph
ate proteoglycans may represent a pool of precursors of anti-angiogeni
c oligosaccharides which may be of primary importance in the regulatio
n of angiogenesis.