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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1996.)
© 2003 American Heart Association, Inc.

Vascular Biology

Molecular Mechanism and Role of Endothelial Monocyte Chemoattractant Protein-1 Induction by Vascular Endothelial Growth Factor

Motoko Yamada; Shokei Kim; Kensuke Egashira; Motohiro Takeya; Tomohiro Ikeda; Osamu Mimura; Hiroshi Iwao

From the Department of Pharmacology (M.Y., S.K., H.I.), Osaka City University Medical School, Osaka; the Department of Ophthalmology (M.Y., T.I., O.M.), Hyogo College of Medicine, Hyogo; the Department of Cardiovascular Medicine (K.E.), Graduate School of Medical Science, Kyusyu University, Fukuoka; and the Second Department of Pathology (M.T.), Kumamoto University School of Medicine, Kumamoto, Japan.

Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp

Objective— We investigated the role of monocyte chemoattractant protein-1 (MCP-1) in vascular endothelial growth factor (VEGF)–induced angiogenesis and vascular permeability and the underlying molecular mechanism of VEGF-induced endothelial MCP-1 expression in vitro and in vivo.

Methods and Results— We used an anti–MCP-1 neutralizing antibody for specific inhibition of MCP-1. VEGF increased tubule formation in the angiogenesis assay and vascular permeability in the Miles assay, and these effects were markedly inhibited by anti–MCP-1 antibody. Using a luciferase MCP-1 promoter-gene assay, we found that the activator protein-1 (AP-1) binding site of the MCP-1 promoter region contributes to the increase in MCP-1 promoter activity by VEGF. To specifically inhibit AP-1, we used recombinant adenovirus containing a dominant-negative c-Jun (Ad-DN-c-Jun). Ad-DN-c-Jun inhibited VEGF-induced endothelial MCP-1 mRNA expression and promoter activity in vitro. In vivo gene transfer of DN-c-Jun into rat carotid artery, with the hemagglutinating virus of the Japan liposome method, significantly blocked VEGF-induced MCP-1 and macrophage/monocyte (ED1) expression in endothelium.

Conclusions— These results reveal that endothelial MCP-1 induced by VEGF seems to participate in angiogenesis, vascular leakage, or arteriosclerosis. AP-1 plays a critical role in the molecular mechanism underlying induction of MCP-1 by VEGF.

Key Words: angiogenesis • vascular permeability • gene transfer • activator protein-1 • dominant-negative mutant

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