Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 23, Issue 11, Pages 1996-2001Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000096208.80992.63
Keywords
angiogenesis; vascular permeability; gene transfer; activator protein-1; dominant-negative mutant
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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.
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