Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesions.
The interaction between macrophages and oxidatively modified low density lipoprotein (Ox-LDL) appears to play a central role in the development of atherosclerosis, not only through foam cell formation but also via the induction of numerous cytokines and growth factors. The current study demonstrated that Ox-LDL upregulated vascular endothelial growth factor (VEGF) mRNA expression in RAW 264 cells, a monocytic cell line, in a time- and concentration-dependent manner and that Ox-LDL stimulated 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 micromol/L lysophosphatidylcholine. Immunohistochemical studies showed that human early atherosclerotic lesions exhibited intense VEGF immunoreactivity in subendothelial macrophage-rich regions of the thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to the lipid core or the neovascularized basal regions of plaque consisting predominantly of smooth muscle cells. High-power-field observation revealed that VEGF was localized in the extracellular space as well as at the macrophage cell surface. These observations suggest the possible involvement of Ox-LDL in the development of human atherosclerosis through VEGF induction in macrophages.
Ramos
M A
MA
Department of Geriatrics, Nagoya University School of Medicine, Japan.
Kuzuya
M
M
Esaki
T
T
Miura
S
S
Satake
S
S
Asai
T
T
Kanda
S
S
Hayashi
T
T
Iguchi
A
A
D016475:3T3 Cells; D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism*; D015152:Blotting, Northern; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008222:Lymphokines / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008077:Lipoproteins, LDL; D008222:Lymphokines; D008244:Lysophosphatidylcholines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C099252:oxidized low density lipoprotein