VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.
VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.
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DOI：
10.1091/mbc.e14-05-0962
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发表时间：
2014-08-15
影响因子：
3.3
通讯作者：
Ponnambalam S
中科院分区：
文献类型：
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作者：
Fearnley GW;Odell AF;Latham AM;Mughal NA;Bruns AF;Burgoyne NJ;Homer-Vanniasinkam S;Zachary IC;Hollstein MC;Wheatcroft SB;Ponnambalam S
VEGF-A亚型通过ERK 1/2蛋白激酶和ATF-2转录因子依赖性机制差异刺激内皮VCAM-1基因表达这种信号转导使VEGF-A亚型特异性刺激白细胞结合内皮细胞，解释了炎症如何受到差异调节。血管内皮生长因子A（VEGF-A）调节血管生理学的许多方面。VEGF-A刺激调节内皮输出的信号转导途径，如细胞迁移、增殖、小管形成和细胞-细胞相互作用。存在多种VEGF-A亚型，但其生物学意义尚不清楚。在这里，我们分析了VEGF-A亚型特异性刺激VCAM-1基因表达，控制内皮细胞-白细胞的相互作用，并表明这是依赖于ERK 1/2和激活转录因子-2（ATF-2）。VEGF-A亚型表现出不同的ERK 1/2和p38 MAPK磷酸化动力学。VEGF-A亚型特异性ERK 1/2激活和核转位的一个关键特征是增加了ATF-2在苏氨酸残基71（T71）上的磷酸化。使用反向遗传学，我们表明ATF-2是VEGF-A刺激的内皮VCAM-1基因表达所需的功能。ATF-2敲低阻断VEGF-A刺激的VCAM-1表达和内皮-白细胞相互作用。ATF-2也是其他内皮细胞输出所必需的，如细胞迁移和小管生成。相比之下，VCAM-1仅对促进内皮细胞-白细胞相互作用至关重要。这项工作提出了一个新的范例，了解可溶性生长因子亚型程序复杂的细胞输出和反应，通过调节信号转导途径。
VEGF-A isoforms differentially stimulate endothelial VCAM-1 gene expression via an ERK1/2 protein kinase and ATF-2 transcription factor–dependent mechanism. Such signal transduction enables VEGF-A isoform–specific stimulation of leukocyte binding to endothelial cells, explaining how inflammation could be differentially regulated. Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell–cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform–specific stimulation of VCAM-1 gene expression, which controls endothelial–leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform–specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A–stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A–stimulated VCAM-1 expression and endothelial–leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial–leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways.