Alginate oligosaccharides cleaved from alginic acid polysaccharides of seaweed were tested to determine their ability to enhance proliferation and migration of human umbilical vein endothelial cells. A mixture of alginate oligosaccharides (5 microg/ml in culture broth) stimulated endothelial cell growth, [(3)H]thymidine uptake and migration in the presence of recombinant vascular endothelial growth factor 165 (VEGF(165)). In contrast, a high concentration mixture of the oligosaccharides ( approximately 100 microg/ml) suppressed cell growth. The stimulatory activity was comparable to that of heparin, with affinity to VEGF(165), and decreased on heparin-induced stimulation. Each effective oligosaccharide had guluronic acid at the reducing end. A mixture of alginate oligosaccharides (5 microg/ml) and the most paragraph signeffective fraction (1 microg/ml) stimulated endothelial cell migration. In the presence of VEGF and heparin, some alginate oligosaccharides with the peripheral guluronic acid demonstrated marked stimulatory effects, and one fraction also showed a migratory effect. These findings indicate novel activities of alginate oligosaccharide(s) in endothelial cell growth and migration and suggest synergistic and/or stabilizing effects on VEGF(165)-dependent stimulation of endothelial cells.