Abstract. Endothelial cell (EC) migration is a critical and initiating event in the formation of new blood vessels and in the repair of injured vessels. Compelling evidence suggests that oxidized low density lipoprotein (LDL) is present in atherosclerotic lesions, but its role in lesion formation has not been defined. We have examined the role of oxidized LDL in regulating the wound-healing response of vascular EC in vitro. Confluent cultures of bovine aortic EC were "wounded" with a razor, and migration was measured after 18 to 24 h as the number of cells moving into the wounded area and the mean distance of cells from the wound edge. Oxidized LDL markedly reduced migration in a concentration-and oxidation-dependent manner. Native LDL or oxidized LDL with a thiobarbituric acid (TBA) reactivity <5 nmol malondialdehyde equivalents/mg cholesterol was not inhibitory; however, oxidized LDL with a TBA reactivity of 8-12 inhibited migration by 75-100%. Inhibition was halfmaximal at 250-300/zg cholesterol/ml and nearly complete at 350--400 #g/ml. The antimigratory activity was not due to cell death since it was completely reversed 16 h after removal of the lipoprotein. The inhibitor molecule was shown to be a lipid; organic solvent extracts of oxidized LDL inhibited migration to nearly the same extent as the intact particle. When LDL was variably oxidized by dialysis against FeSO4 or CuSO,, or by UV irradiation, the inhibitory activity correlated with TBA reactivity and total lipid peroxides, but not with electrophoretic mobility or fluorescence (360 ex/430 em). This indicates that a lipid hydroperoxide may be the active species. These results suggest the possibility that oxidized LDL may limit the healing response of the endothelium after injury.NDOTHELIAL cell (EC) t migration and proliferation are critical processes in the formation of blood vessels and in the repair of injured vessels. In the earliest report that distinguished between the roles of migration and proliferation in vivo, Schoefl (52) observed that EC migration was the initiating, and potentially rate-limiting event in the regeneration of capillaries after tissue injury. Ausprunk and Folkman (2) likewise observed that migrating EC initiated the extension of capillary "buds" towards angiogenic factors. Both laboratories concluded that migrating cells at the tip of a new capillary started the process and that subsequent EC proliferation filled in the gaps left behind by vacated cells. The same EC processes are involved in the repair of major blood vessels after the physical trauma induced by balloon angioplasty, vascular reconstruction or replacement, and organ implantation. Haudenschild and Schwartz (23) showed that removal of the endothelium from a rat thoracic aorta with a balloon catheter was followed by a gradual regeneration of the endothelial lining. In this system, too, the repair process was initiated by EC migration and followed by proliferation. Reidy and Schwartz (46) served that a very narrow wound to the endothelium of the rat aorta, ~1 t...