Serum response factor is a critical requirment for VEGF signaling in endothelial cells and VEGF-induced angiogenesis
Serum response factor is a critical requirment for VEGF signaling in endothelial cells and VEGF-induced angiogenesis
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DOI：
10.1096/fj.03-1232fje
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发表时间：
2004-06-01
期刊：
影响因子：
4.8
通讯作者：
Tarnawski, AS
中科院分区：
文献类型：
--
作者：
Chai, JY;Jones, MK;Tarnawski, AS
血管生成是一种新的毛细血管形成，对胚胎发育、伤口愈合和肿瘤生长至关重要。血管内皮生长因子(VEGF)通过激活内皮细胞的迁移和增殖来诱导血管生成。血清反应因子(SRF)是一种对胚胎发育和激活即刻早期基因表达起重要作用的转录因子。SRF在血管内皮细胞生物学和血管生成中的作用尚不清楚。在这里，我们证明了SRF是血管内皮细胞中血管内皮生长因子信号的下游介体，也是血管内皮生长因子诱导血管生成的关键条件。下调人和大鼠内皮细胞SRF蛋白水平可阻断血管内皮生长因子诱导的体外血管生成，损害血管内皮细胞的迁移和增殖，抑制血管内皮生长因子诱导的肌动蛋白聚合和即刻早期基因表达。大鼠胃溃疡组织注射SRF反义表达载体后，肉芽组织中血管生成受到明显抑制。在机制上，本研究还发现，血管内皮细胞生长因子通过Rho-肌动蛋白和MEK-ERK依赖的信号通路促进SRF的表达和核转位，并增加SRF与DNA的结合活性。这些发现具有潜在的治疗意义，例如，局部抗SRF治疗可能会抑制对肿瘤生长至关重要的血管生成。
Angiogenesis, new capillary blood vessel formation, is essential for embryonic development, wound healing, and cancer growth. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating endothelial cell migration and proliferation. Serum response factor (SRF) is a transcription factor important for embryonic development and activation of immediate early gene expression. The roles of SRF in endothelial cell biology and angiogenesis have not been explored. Here we demonstrate that SRF is a downstream mediator of VEGF signaling in endothelial cells and a critical requirement for VEGF-induced angiogenesis. Knockdown of SRF protein levels in human and rat endothelial cells abolished VEGF-induced in vitro angiogenesis, impaired endothelial cell migration and proliferation, and inhibited VEGF-induced actin polymerization and immediate early gene expression. Injection of SRF antisense expression plasmid into gastric ulcers in rats significantly inhibited in vivo angiogenesis in granulation tissue. Mechanistically, this study also revealed that VEGF promotes SRF expression and nuclear translocation and increases SRF binding activity to DNA in endothelial cells through both Rho-actin and MEK-ERK dependent signaling pathways. These findings have potential therapeutic implications, e.g., local anti-SRF treatment may inhibit angiogenesis crucial for tumor growth.