Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway.
Aminoacyl-Transfer RNA Synthetase Deficiency Promotes Angiogenesis via the Unfolded Protein Response Pathway.
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DOI：
10.1161/atvbaha.115.307087
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Weinstein BM
中科院分区：
文献类型：
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作者：
Castranova D;Davis AE;Lo BD;Miller MF;Paukstelis PJ;Swift MR;Pham VN;Torres-Vázquez J;Bell K;Shaw KM;Kamei M;Weinstein BM
了解正常和病理性血管生成的调控机制具有重要的科学和临床意义。在这份报告中，我们证明了两种不同的氨基酰基tRNA合成酶，苏氨酰tRNA合成酶(Tarsy58)或异亮氨酰tRNA合成酶(Iarsy68)的突变，在发育中的斑马鱼中导致类似的分支血管生成增加。未折叠蛋白反应(UPR)途径是由氨基酰tRNA合成酶缺陷激活的，我们发现UPR基因ATF4、ATF6和XBP1以及关键的促血管生成配体血管内皮生长因子(VEGFAA)在tarsy58和iarsy68突变体中都上调。最后，我们证明了UPR途径的PERK-ATF4臂对于tarsy58突变体中观察到的高VEGFAA水平和增加血管生成都是必要的。我们的结果表明，内质网(ER)应激通过UPR途径依赖的VEGFa上调作为促血管生成信号。
Understanding the mechanisms regulating normal and pathologic angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in two different aminoacyl tRNA synthetases, threonyl tRNA synthetase (tarsy58) or isoleucyl tRNA synthetase (iarsy68), lead to similar increased branching angiogenesis in developing zebrafish. The Unfolded Protein Response (UPR) pathway is activated by aminoacyl tRNA synthetase deficiencies, and we show that UPR genes atf4, atf6, and xbp1, as well as the key pro-angiogenic ligand vascular endothelial growth factor (vegfaa), are all up-regulated in tarsy58 and iarsy68 mutants. Finally, we show that the PERK-ATF4 arm of the UPR pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tarsy58 mutants. Our results suggest that endoplasmic reticulum (ER) stress acts as a pro-angiogenic signal via UPR pathway-dependent up-regulation of vegfaa.