INDUCTION OF MACROPHAGE VEGF IN RESPONSE TO OXIDIZED LDL AND VEGF ACCUMULATION IN HUMAN ATHEROSCLEROTIC LESIONS

The interaction between macrophages and oxidatively modified low densi ty lipoprotein (Ox-LDL) appears to play a central role in the developm ent of atherosclerosis, not only through foam cell formation but also via the induction of numerous cytokines and growth factors. The curren t study demonstrated that Ox-LDL upregulated vascular endothelial grow th factor (VEGF) mRNA expression in RAW 264 cells, a monocytic cell li ne, in a time- and concentration-dependent manner and that Ox-LDL stim ulated VEGF protein secretion from the cells. Lysophosphatidylcholine, a component of Ox-LDL, also enhanced VEGF mRNA expression in RAW 264 cells and VEGF secretion from RAW 264 cells, with a maximal effect at a concentration of 10 mu mol/L lysophosphatidylcholine. Immunohistoche mical studies showed that human early atherosclerotic lesions exhibite d intense VEGF immunoreactivity in subendothelial macrophage-rich regi ons of the thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to the lipid cor e or the neovascularized basal regions of plaque consisting predominan tly of smooth muscle cells. High-power-field observation revealed that VEGF was localized in the extracellular space as well as at the macro phage cell surface. These observations suggest the possible involvemen t of Ox-LDL in the development of human atherosclerosis through VEGF i nduction in macrophages.