Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3
Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3
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DOI：
10.1182/blood-2009-07-233478
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发表时间：
2010-03-25
期刊：
影响因子：
20.3
通讯作者：
Minami, Takashi
中科院分区：
文献类型：
--
作者：
Suehiro, Jun-ichi;Hamakubo, Takao;Minami, Takashi
内皮细胞活化和功能障碍是许多血管疾病的基础，包括动脉粥样硬化、肿瘤生长和脓毒症。反过来，内皮细胞活化主要在基因转录水平介导。在这里，我们表明，在响应几个激活激动剂，包括血管内皮生长因子（VEGF），肿瘤坏死因子-α，凝血酶，内皮细胞表现出快速和深刻的诱导早期生长反应（EGR）基因的EGR-1和EGR-3。在VEGF处理的内皮细胞中，与Egr-1相比，Egr-3的诱导作用更大且更长。VEGF介导的Egr-3刺激涉及NFATc、血清反应因子和CREB与Egr-3上游启动子区各自共有基序的诱导性结合。敲低Egr-3显著损害VEGF介导的内皮细胞增殖、迁移和管形成，并阻断VEGF诱导的单核细胞粘附。Egr-3敲除废除VEGF介导的血管生长从离体主动脉环和衰减基质胶栓塞血管化和黑色素瘤肿瘤生长在体内。总之，这些发现表明，Egr-3是活化内皮细胞中VEGF信号传导的关键决定因素。因此，Egr-3代表VEGF介导的血管病变疾病的潜在治疗靶点。（血。2010; 115：2520-2532）
Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis, tumor growth, and sepsis. Endothelial cell activation, in turn, is mediated primarily at the level of gene transcription. Here, we show that in response to several activation agonists, including vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha, and thrombin, endothelial cells demonstrate rapid and profound induction of the early growth response (Egr) genes egr-1 and egr-3. In VEGF-treated endothelial cells, induction of Egr-3 was far greater and more prolonged compared with Egr-1. VEGF-mediated stimulation of Egr-3 involved the inducible binding of NFATc, serum response factor, and CREB to their respective consensus motifs in the upstream promoter region of Egr-3. Knockdown of Egr-3 markedly impaired VEGF-mediated proliferation, migration, and tube formation of endothelial cells and blocked VEGF-induced monocyte adhesion. Egr-3 knockdown abrogated VEGF-mediated vascular outgrowth from ex vivo aortic rings and attenuated Matrigel plug vascularization and melanoma tumor growth in vivo. Together, these findings suggest that Egr-3 is a critical determinant of VEGF signaling in activated endothelial cells. Thus, Egr-3 represents a potential therapeutic target in VEGF-mediated vasculopathic diseases. (Blood. 2010; 115: 2520-2532)