Low-sulphated oligosaccharides derived from heparan sulphate 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 anti-angiogenic 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 anti-angiogenic 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.
Hahnenberger
R
R
Department of Ophthalmology, Akademiska Sjukhuset, Uppsala, Sweden.
Jakobson
A M
AM
Ansari
A
A
Wehler
T
T
Svahn
C M
CM
Lindahl
U
U
D000818:Animals; D016667:Bacterial Capsules; D002240:Carbohydrate Sequence; D002642:Chick Embryo; D002850:Chromatography, Gel; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D009844:Oligosaccharides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
D006497:Heparan Sulfate; D009844:Oligosaccharides; D011135:Polysaccharides, Bacterial; C050673:capsular polysaccharide K5