VEGF stimulates HDAC7 phosphorylation and cytoplasmic accumulation modulating matrix metalloproteinase expression and angiogenesis.
VEGF stimulates HDAC7 phosphorylation and cytoplasmic accumulation modulating matrix metalloproteinase expression and angiogenesis.
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DOI：
10.1161/atvbaha.108.172528
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Jin ZG
中科院分区：
文献类型：
--
作者：
Ha CH;Jhun BS;Kao HY;Jin ZG
组蛋白乙酰化/去乙酰化在基因表达调控、组织生长发育中起着重要作用。特别是组蛋白脱乙酰酶7（HDAC 7），其是IIa类HDAC的成员，在维持血管完整性中至关重要。然而，HDAC 7是否参与血管内皮信号传导和血管生成的过程仍不清楚。在这里，我们研究了HDAC 7在血管内皮生长因子（VEGF）信号传导和血管生成中的作用。我们首次发现，VEGF以剂量和时间依赖性的方式刺激HDAC 7在Ser 178，Ser 344和Ser 479位点的磷酸化，这导致HDAC 7在细胞质中的积累。利用药物抑制剂、siRNA和携带显性失活突变体的腺病毒，我们发现磷脂酶Cγ/蛋白激酶C/蛋白激酶D1（PKD 1）依赖的信号通路介导了血管内皮生长因子对HDAC 7的磷酸化和胞浆蓄积。腺病毒编码的突变体HDAC 7特异性缺乏PKD 1依赖性磷酸化的EC感染，抑制VEGF诱导的血管生成基因的表达，包括基质金属蛋白酶MT 1-MMP和MMP 10。此外，HDAC 7及其靶基因参与VEGF刺激的内皮细胞迁移、管形成和微血管出芽。我们的研究结果表明，VEGF刺激PKD 1依赖HDAC 7磷酸化和细胞质积累在内皮细胞调节基因表达和血管生成。
Histone acetylation/deacetylation plays an important role in the control of gene expression, tissue growth and development. In particular, histone deacetylases 7 (HDAC7), a member of class IIa HDACs, is crucial in maintaining vascular integrity. However, whether HDAC7 is involved in the processes of vascular endothelial signaling and angiogenesis remains unclear. Here, we investigated the role of HDAC7 in vascular endothelial growth factor (VEGF) signaling and angiogenesis. We show for the first time that VEGF stimulated phosphorylation of HDAC7 at the sites of Ser178, Ser344, and Ser479 in a dose- and time-dependent manner, which leads to the cytoplasmic accumulation of HDAC7. Using pharmacological inhibitors, siRNA and adenoviruses carrying dominant-negative mutants, we found that phospholipase Cγ/protein kinase C/protein kinase D1 (PKD1)-dependent signal pathway mediated HDAC7 phosphorylation and cytoplasmic accumulation by VEGF. Infection of ECs with adenoviruses encoding a mutant of HDAC7 specifically deficient in PKD1-dependent phosphorylation, inhibited VEGF-induced angiogenic gene expression, including matrix metalloproteinases MT1-MMP and MMP10. Moreover, HDAC7 and its targeting genes were involved in VEGF-stimulated endothelial cell migration, tube formation and microvessel sprouting. Our results demonstrate that VEGF stimulates PKD1-dependent HDAC7 phosphorylation and cytoplasmic accumulation in endothelial cells modulating gene expression and angiogenesis.