In vivo evidence of angiogenesis induced by transcription factor ets-1 - Ets-1 is located upstream of angiogenesis cascade
In vivo evidence of angiogenesis induced by transcription factor ets-1 - Ets-1 is located upstream of angiogenesis cascade
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DOI：
10.1161/01.cir.0000130643.41587.db
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发表时间：
2004-06-22
期刊：
影响因子：
37.8
通讯作者：
Morishita, R
中科院分区：
文献类型：
--
作者：
Hashiya, N;Jo, N;Morishita, R
转录因子ets-1调节金属蛋白酶基因的转录，金属蛋白酶基因的活性是基质降解和内皮细胞迁移所必需的。然而，没有研究表明ets-1本身在体内具有血管生成作用。因此，我们研究了（1）在大鼠后肢缺血模型中ets-1基因的过度表达对血管生成的影响，以及（2）ets-1如何诱导血管生成。方法和结果-在这项研究中，我们使用了HVJ-脂质体方法，这是非常有效的转染，来检测人ets-1基因。转染后4周，与对照组相比，转染人ets-1基因的后肢毛细血管密度和血流量显著增加。这些数据清楚地表明ets-1具有在体内刺激血管生成的能力。为了阐明ets-1诱导血管生成的分子机制，我们特别关注肝细胞生长因子（HGF）和血管内皮生长因子（VEGF）的表达，这两种有效的血管生成生长因子，因为这两种基因的启动子区域都含有ets结合位点。有趣的是，ets-1过表达上调大鼠后肢组织中HGF和VEGF的浓度。更重要的是，针对HGF和VEGF的中和抗体的施用减弱了ets-1诱导的血流量和BrdU阳性细胞的增加。通过使用人血管平滑肌cells.Conclusions -本研究表明，ets-1通过诱导血管生成生长因子（VEGF和HGF）来调节血管生成。ets的过表达可能为外周动脉疾病的治疗提供一种新的策略。
Background - A transcription factor, ets-1, regulates the transcription of metalloproteinase genes, the activity of which is necessary for matrix degradation and the migration of endothelial cells. However, no study has demonstrated that ets-1 itself has an angiogenic action in vivo. Thus, we examined ( 1) the effects of overexpression of the ets-1 gene on angiogenesis in a rat hindlimb ischemia model, and ( 2) how ets-1 induced angiogenesis.Methods and Results - In this study, we used the HVJ-liposome method, which is highly effective for transfection, to transfect the human ets-1 gene. At 4 weeks after transfection, the capillary density and blood flow were significantly increased in a hindlimb transfected with the human ets-1 gene compared with control. These data clearly demonstrated that ets-1 has the ability to stimulate angiogenesis in vivo. To elucidate the molecular mechanisms by which ets-1 induced angiogenesis, we focused especially on the expression of hepatocyte growth factor (HGF) and vascular endothelial growth factor ( VEGF), potent angiogenic growth factors, because the promoter regions of both genes contain ets binding sites. Interestingly, overexpression of ets-1 upregulated both tissue HGF and VEGF concentrations in rat hindlimb. More importantly, administration of neutralizing antibody against HGF and VEGF attenuated the increase in blood flow and BrdU-positive cells induced by ets-1. Upregulation of HGF and VEGF by ets-1 was also confirmed by in vitro experiments using human vascular smooth muscle cells.Conclusions - The present study demonstrated that ets-1 regulated angiogenesis through the induction of angiogenic growth factors ( VEGF and HGF). Overexpression of ets may provide a new therapeutic strategy to treat peripheral arterial disease.