Endothelial cell (EC) migration is a regulatory event in the formation and repair of blood vessels. Although serum contains substantial promigratory activity, the responsible components and especially the role of lipoproteins have not been determined. We examined the effect of plasma high-density lipoprotein (HDL) on the movement of ECs in vitro. Confluent cultures of bovine aortic ECs in serum-free medium were "wounded," and migration was measured after 24 hours. HDL stimulated migration in a concentration-dependent manner with a half-maximal response at 25 to 40 micrograms cholesterol per milliliter and a maximal twofold stimulation at approximately 150 micrograms cholesterol per milliliter. HDL-stimulated migration was not due to cell proliferation, since migration was increased in the presence of hydroxyurea at a concentration that blocked proliferation. At optimal concentrations, HDL was at least as stimulatory as basic fibroblast growth factor (FGF). However, the activity of HDL was not due to contamination by basic FGF, since antibodies to basic FGF did not block HDL-stimulated movement and since the maximum promigratory activities of basic FGF and HDL were additive. These results indicate that HDL and basic FGF may use distinct signaling pathways to initiate EC movement. This possibility was confirmed by results showing that pertussis toxin suppressed basic FGF-stimulated but not HDL-stimulated EC motility and that inhibitors of phospholipase A2, aristolochic acid and ONO-RS-082, also blocked the promigratory activity of basic FGF but had no effect on the activity of HDL.(ABSTRACT TRUNCATED AT 250 WORDS)