Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor

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.