Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin
Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin
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DOI：
10.1038/emboj.2011.298
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发表时间：
2011-10-19
期刊：
影响因子：
11.4
通讯作者：
Urbich, Carmen
中科院分区：
文献类型：
--
作者：
Kaluza, David;Kroll, Jens;Urbich, Carmen
组蛋白去乙酰化酶（hdac）使组蛋白和非组蛋白去乙酰化，从而影响蛋白质活性和基因表达。细胞质IIb类HDAC6在内皮细胞（ECs）中的调节和功能在很大程度上未被探索。在这里，我们证明HDAC6在缺氧时上调，并且对血管生成至关重要。ECs中HDAC6的沉默减少了体外萌发和迁移以及体内基质塞中功能性血管网络的形成。HDAC6调节斑马鱼血管形成，HDAC6缺陷小鼠基质塞灌注血管形成减少。一致地，野生型HDAC6的过表达增加了球体的发芽。HDAC6的功能需要催化活性，但不依赖于泛素结合和α -微管蛋白的去乙酰化。相反，我们发现HDAC6与ECs中的肌动蛋白重塑蛋白相互作用并使其去乙酰化，这对斑马鱼血管形成至关重要，并介导HDAC6的血管生成作用。总之，我们发现HDAC6在体内和体外血管生成中都是必需的，涉及到调节EC迁移和发芽的接触蛋白的相互作用和去乙酰化。
Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of alpha-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting.