15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression
15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression
复制标题
DOI：
10.1182/blood-2009-09-241802
复制
发表时间：
2010-03-11
期刊：
影响因子：
20.3
通讯作者：
Rao, Gadiparthi N.
中科院分区：
文献类型：
--
作者：
Kundumani-Sridharan, Venkatesh;Niu, Jixiao;Rao, Gadiparthi N.
为了理解15（S）-羟基二十碳四烯酸[15（S）-HETE]诱导血管生成的机制，我们研究了Egr-1的作用。15（S）-HETE以时间依赖性方式诱导人真皮微血管内皮细胞（HDMVEC）中Egr-1的表达。通过其显性负突变体的强制表达阻断Egr-1减弱了15（S）-HETE诱导的HDMVEC迁移和管形成以及基质胶栓塞血管生成。15（S）-HETE诱导的Egr-1表达需要Src激活。此外，腺病毒介导的Src显性失活突变体的表达阻断了15（S）-HETE对HDMVEC迁移和管形成以及Matrigel栓血管生成的作用。15（S）-HETE通过Src介导的Egr-1的产生快速诱导成纤维细胞生长因子-2（FGF-2）表达。FGF-2启动子的克隆和突变分析表明，15（S）-HETE诱导FGF-2表达需要靠近转录起始位点的Egr-1结合位点。中和抗体介导的FGF-2功能抑制也减弱了15（S）-HETE对HDMVEC迁移和管形成以及基质胶栓塞血管生成的作用。此外，与野生型小鼠相反，12/15-LOX-/-小鼠表现出响应于AA的基质胶栓血管生成减少，其被15（S）-HETE拯救。基于这些观察，我们得出结论，15（S）-HETE诱导的血管生成需要Src介导的Egr-1依赖性FGF-2的快速诱导。这些发现提示15（S）-HETE可能是动脉粥样硬化和再狭窄相关的病理性血管生成的潜在内源性调节剂。（血。2010; 115：2105-2116）
To understand the mechanisms underlying 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]-induced angiogenesis, we studied the role of Egr-1. 15(S)-HETE induced Egr-1 expression in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Blockade of Egr-1 via forced expression of its dominant-negative mutant attenuated 15(S)-HETE -induced HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. 15(S)-HETE induced Egr-1 expression requires Src activation. In addition, adenovirus-mediated expression of dominant-negative mutant of Src blocked 15(S)-HETE's effects on migration and tube formation of HDMVECs and Matrigel plug angiogenesis. 15(S)-HETE induced fibroblast growth factor-2 (FGF-2) expression rapidly via Src-mediated production of Egr-1. Cloning and mutational analysis of FGF-2 promoter revealed that Egr-1 binding site proximal to transcription start site is required for 15(S)-HETE induced FGF-2 expression. Neutralizing antibody-mediated suppression of FGF-2 function also attenuated the effects of 15(S)-HETE on HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. Furthermore, in contrast to wild-type mice, 12/15-LOX-/- mice exhibited decreased Matrigel plug angiogenesis in response to AA, which was rescued by 15(S)-HETE. On the basis of these observations, we conclude that 15(S)-HETE-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2. These findings may suggest that 15(S)-HETE could be a potential endogenous regulator of pathologic angiogenesis associated with atherosclerosis and restenosis. (Blood. 2010; 115: 2105-2116)