2000 Fiscal Year Final Research Report Summary
ROLE OF VEGF IN ATHEROGENESIS
| Project/Area Number |
10671061
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | NAGOYA UNIVERSITY |
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Principal Investigator |
KUZUYA Masafumi MEDICINE, NAGOYA UNIVERSITY, ASSISTANT PROFESSOR, 医学部, 講師 (10283441)
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| Co-Investigator(Kenkyū-buntansha) |
KOIKE Teruhiko MEDICINE, NAGOYA UNIVERSITY, MEDICAL STAFF, 医学部, 医員
IGUCHI Akihisa MEDICINE, NAGOYA UNIVERSITY, PROFESSOR, 医学部, 教授 (20109763)
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| Project Period (FY) |
1998 – 2000
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| Keywords | atherosclerosis / vascular endothelial cell / vascular endothelial growth factor / oxidized low density lipoprotein / macrophage / VEGF receptor / glutathione / angiogenesis |
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| Research Abstract |
Immunohistochemical studies showed that human early atherosclerotic lesions exhibited intensive vascular endothelial growth factor (VEGF) immunoreactivity in subendothelial macrophage-rich regions of thickened intima. In atherosclerotic plaques, VEGF staining was also observed in foam cell-rich regions adjacent to lipid core or neovascularized basal regions of plaque consisting predominantly of smooth muscle cells. High powered field observation revealed that VEGF was localized in extracellular space as well as macrophage cell surface. These observations suggest the possible involvement of oxidized loe density lipoprtein (Ox-LDL) in the development of human atherosclerosis through VEGF induction in macrophages. We also demonstrated that Ox-LDL upregulated VEGF mRNA expression in RAW 264 cells, monocytic cell line, in a time and concentration dependent manner, and that Ox-LDL stimulated the VEGF protein secretion from the cells.
We hypothesized that VEGF in subendothelial macrophage-rich
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regions adjacent to endothelial cells at the luminal surface may participate in the maintenance and repair of the lumen endothelium. To test our hypothesis we examined whether VEGF protects the toxicity of Ox-LDL to cultured endothelial cells derived from bovine aorta (BAECs). BAECs preincubation with VEGF prevented Ox-LDL toxicity in a preincubation time- and VEGF concentration-dependent manner. Incubation of BAECs with VEGF increased intracellular glutathione (GSH) in a time-dependent manner. Combined addition of VEGF and L-buthionine sulfoximine, a GSH synthesis inhibitor, reversed GSH level and the protective effect of VEGF on Ox-LDL-induced cytotoxicity. Placenta growth factor, which ligates to VEGF Fit-1 receptor but not KDR/Flk-1, failed to prevent Ox-LDL toxicity and had no effect on intracellular GSH level. Anti- KDR/Flk-1 antibody completely blocked these activities of VEGF.These results suggest that VEGF prevents Ox-LDL-induced endothelial cell damage via intracellular GSH-dependent mechanism through KDR/Flk-1 receptor. Less
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Research Products
(25 results)
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[Publications] Masafumi Kuzuya, Miguel A Ramos, Shigeru Kanda, Teruhiko Koike, Toshinobu Asai, Keiko Maeda, Kenya Shitara, Masabumi Shibuya, Akihisa Iguchi.: "VEGF Protects Toxicity of Oxidized LDL to Endothelial Cell via Intracellular Glutathione-Dependent Mechanism through KDR Receptor"Arteriosclerosis, Thrombosis, and Vascular Biology. (in press). (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Ai, S., Kuzuya, M., Koike, T., Asai, T., Kanda, S., Maeda, K., Shibata, T., Iguchi, A.: "Rho-Rho kinase is involved in smooth muscle cell migration though myosin light chain phosphorylation-dependent and independent pathways."Atherosclerosis. (in press). (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Koike, T., Kuzuya, M., Asai, T., Kanda, S., Cheng, XW., Watanabe, K., Banno, Y., Nozawa, Y., Iguchi, A.: "Activation of MMP-2 by Clostridium difficile Toxin B in bovine smooth muscle cells."Biochem.Biophys.Res.Commun. 277. 43-46 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Nakayama, S., Klugbauer, N., Kabeya, Y., Smith, L.M., Hofmann, F., Kuzuya, M.: "The alpha 1-subunit of smooth muscle Ca^<2+> channel preserves multiple open states induced by depolaruzation."J.Physiol.(London). 526. 47-56 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Horiba, M, Kadomatsu, K., Nakamura, E., Muramatsu, H., Ikematsu, S., Sakuma, S., Hayashi, K., Yuzawa, Y., Matsuo, S., Kuzuya, M., Kaname, T., Hirai, M., Saito, H., and Muramatsu, T.: "Neointima formation in a restenosis model is suppressed in midkine-deficient mice."J.Clin.Invest.. 105. 489-495 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Kanda, S., Kuzuya, M., Ramos, A.M., Koike, T., Yoshino, K., Ikeda, S., Iguchi, A.: "Matrix metalloproteinase and αvβ3 integrin-dependent vascular smooth muscle cell invasion through the type I collagen lattice."Arteriosclerosis, Thrombosis, and Vascular Biology. 20. 998-1005 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Kuzuya, M., Satake, S., Ramos, A.M., Kanda, S., Koike, T., Yoshino, Y., Ikeda, S., Iguchi, A.: "Induction of apoptotic cell death in vascular endothelial cells cultured in three-dimensional collagen lattice."Exp.Cell Res. 248. 498-508 (1999)
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[Publications] Kuzuya, M., Satake, S., Ai, S., Asai, T., Kanda, S., Ramos, M.A., Miura, H., Ueda, M., Iguchi, A.: "Inhibition of angiogenesis on glycated collagen lattices."Diabetologia. 41. 491-499 (1998)
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[Publications] Ramos, M.A., Kuzuya, M., Esaki, T., Miura, S., Satake, S., Asai, T., Kanda, S., Hayashi, T., Iguchi, A.: "Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesion."Arteriosclerosis, Thrombosis, and Vascular Biology. 18. 1188-1196 (1998)
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[Publications] Satake, S., Kuzuya, M., Miura, H., Asai, T., Ramos, M.A., Muraguchi, M., Ohmoto, Y., Iguchi, A.: "Up-regulation of vascular endothelial growth factor in response to glucose deprivation."Biology of the Cell. 90. 161-168 (1998)
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