Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor
Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor
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DOI：
10.1161/01.atv.0000096208.80992.63
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发表时间：
2003-11-01
影响因子：
8.7
通讯作者：
Iwao, H
中科院分区：
文献类型：
--
作者：
Yamada, M;Kim, S;Iwao, H
目的-我们研究了单核细胞趋化蛋白-1（MCP- 1）在血管内皮生长因子（VEGF）诱导的血管生成和血管通透性中的作用，以及VEGF诱导的内皮MCP- 1表达的潜在分子机制。方法和结果-我们使用抗MCP- 1中和抗体特异性抑制MCP- 1。VEGF在血管生成试验中增加小管形成，在Miles试验中增加血管通透性，并且这些作用被抗MCP- 1抗体显著抑制。使用荧光素酶MCP- 1启动子基因测定，我们发现MCP- 1启动子区域的激活蛋白-1（AP- 1）结合位点有助于VEGF增加MCP- 1启动子活性。为了特异性抑制AP- 1，我们使用了含有显性阴性c-Jun的重组腺病毒（Ad-DN-c-Jun）. Ad- DN- c- Jun在体外抑制VEGF诱导的内皮MCP- 1 mRNA表达和启动子活性。在体内基因转移DN- c- Jun到大鼠颈动脉，与日本脂质体方法的血凝病毒，显着阻断VEGF诱导的MCP- 1和巨噬细胞/单核细胞（ED 1）在endothelial.Conclusions表达-这些结果表明，内皮MCP- 1诱导的VEGF似乎参与血管生成，血管渗漏，或动脉硬化。AP- 1在VEGF诱导MCP- 1的分子机制中起关键作用。
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.