HDAC6 and ERK/ADAM17 Regulate VEGF-Induced NOTCH Signaling in Lung Endothelial Cells.
HDAC6 and ERK/ADAM17 Regulate VEGF-Induced NOTCH Signaling in Lung Endothelial Cells.
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DOI：
10.3390/cells12182231
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发表时间：
2023-09-08
期刊：
影响因子：
6
通讯作者：
Sampath, Venkatesh
中科院分区：
文献类型：
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作者：
Xia, Sheng;Menden, Heather L.;Mabry, Sherry M.;Sampath, Venkatesh
血管生成在多种生理和病理过程中发挥着重要作用，并受血管内皮生长因子的调控。组蛋白去乙酰酶6(HDAC6)是一种IIB类HDAC，通过去乙酰化来调节细胞质信号转导，是调控血管生成的靶点。我们研究了一种假说，即血管内皮生长因子诱导的内皮细胞(EC)Noch信号是由HDAC6通过NICD乙酰化来调节的。在肺内皮细胞(EC)中，血管内皮生长因子诱导的NICD转录反应的激活受ERK1/2和ADAM17调节，并需要DLL4。当HDAC6抑制诱导NICD的乙酰化并稳定NICD时，它抑制了Notch转录反应所需的NICD-SNW1结合。体外实验表明，HDAC6抑制抑制肺内皮细胞血管生成，全身应用HDAC6抑制剂处理的新生小鼠显著改变了血管生成和肺泡化。这些发现揭示了HDAC6通过乙酰化和抑制转录调节因子NICD和SNW1来调节血管生成的作用。
Angiogenesis plays a critical role in various physiological and pathological processes and is regulated by VEGF. Histone Deacetylase 6 (HDAC6) is a class IIB HDAC that regulates cytoplasmic signaling through deacetylation and is emerging as a target for modulating angiogenesis. We investigated the hypothesis that VEGF-induced endothelial cell (EC) NOTCH signaling is regulated by HDAC6 through acetylation of NOTCH intracellular cytoplasmic domain (NICD). In pulmonary endothelial cells (EC), VEGF-induced activation of the NICD transcriptional response was regulated by ERK1/2 and ADAM 17 and required DLL4. While HDAC6 inhibition induced the acetylation of NICD and stabilized NICD, it repressed NICD-SNW1 binding required for the NOTCH transcriptional responses. In vitro experiments showed that HDAC6 inhibition inhibited lung EC angiogenesis, and neonatal mice treated with a systemic HDAC6 inhibitor had significantly altered angiogenesis and alveolarization. These findings shed light on the role of HDAC6 in modulating VEGF-induced angiogenesis through acetylation and repression of the transcriptional regulators, NICD and SNW1.
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影响因子：
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