Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity
Combinatory action of VEGFR2 and MAP kinase pathways maintains endothelial-cell integrity
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VEGFR2 和 MAP 激酶途径的联合作用维持内皮细胞完整性
DOI：
10.1038/cr.2011.41
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发表时间：
2011-03
期刊：
影响因子：
44.1
通讯作者：
Lin, Shuo
中科院分区：
文献类型：
--
作者：
Zhong, Hanbing;Wang, Danyang;Wang, Nan;Rios, Yesenia;Huang, Haigen;Li, Song;Wu, Xinrong;Lin, Shuo
血管通常保持固定的管腔直径，其稳定的结构对血管功能至关重要。然而，对控制血管内径维持和内皮细胞完整性的分子机制知之甚少。我们用化学遗传学的方法在斑马鱼胚胎中研究了这个问题。用GFP特异性标记内皮细胞的TG(kdrl：GRCFP)zn1转基因活胚胎筛选小分子文库。通过分析化合物在管腔形成后对胚胎血管形态和功能的影响，PP1被认为是一种潜在的Src激酶抑制剂，能够通过干扰内皮细胞的完整性来特异性地缩小血管管腔的大小。这种抑制作用不是由于Src或一般的血管内皮生长因子信号的抑制，因为另一种Src抑制剂和Src吗啉以及几种VEGFR抑制剂都不能产生类似的表型。在分析了一组22个具有代表性的哺乳动物蛋白激酶并调查了已发表的数据之后，我们选择了几个可能的新候选基因。对这些候选激酶抑制剂的组合分析证实，PP1通过抑制VEGFR2和MAP激酶途径而导致内皮细胞崩溃。更重要的是，两种临床批准的药物Dasatinib和Sunitinib的联合使用产生了相同的表型。这是第一次利用化学遗传学方法阐明控制内皮完整性维持的通路，表明内皮完整性是由VEGFR2和MAP激酶通路共同作用控制的。我们的研究结果还表明，两种抗癌药物联合应用可能会对循环系统产生副作用。
Blood vessels normally maintain stereotyped lumen diameters and their stable structures are crucial for vascular function. However, very little is known about the molecular mechanisms controlling the maintenance of vessel diameters and the integrity of endothelial cells. We investigated this issue in zebrafish embryos by a chemical genetics approach. Small molecule libraries were screened using live Tg (kdrl: GRCFP) zn1 transgenic embryos in which endothelial cells are specifically labeled with GFP. By analyzing the effects of compounds on the morphology and function of embryonic blood vessels after lumen formation, PP1, a putative Src kinase inhibitor, was identified as capable of specifically reducing vascular lumen size by interrupting endothelial-cell integrity. The inhibitory effect is not due to Src or general VEGF signaling inhibition because another Src inhibitor and Src morpholino as well as several VEGFR inhibitors failed to produce a similar phenotype. After profiling a panel of 22 representative mammalian kinases and surveying published data, we selected a few possible new candidates. Combinational analysis of these candidate kinase inhibitors established that PP1 induced endothelial collapse by inhibiting both the VEGFR2 and MAP kinase pathways. More importantly, combinatory use of two clinically approved drugs Dasatinib and Sunitinib produced the same phenotype. This is the first study to elucidate the pathways controlling maintenance of endothelial integrity using a chemical genetics approach, indicating that endothelial integrity is controlled by the combined action of the VEGFR2 and MAP kinase pathways. Our results also suggest the possible side effect of the combination of two anticancer drugs on the circulatory system.
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