Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines
Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines
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DOI：
10.1016/j.bbadis.2014.10.007
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发表时间：
2014-12-01
影响因子：
6.2
通讯作者：
Tong, XiaoYong
中科院分区：
文献类型：
--
作者：
Chen, Lili;Hou, Xiuyun;Tong, XiaoYong
血管内皮细胞（EC）负责缺血后血管生成，这是一个由活性氧调节的过程。最近的研究表明，内皮Nox4为基础的NADPH氧化酶可能有关键作用。本研究旨在探讨内皮细胞Nox 4在缺血诱导的血管生成中的作用，并探讨其可能的机制。使用在内皮中特异性过表达人Nox 4野生型（EWT）或其显性阴性形式P437 H（EDN）的小鼠系。使用非转基因同窝小鼠（NTg）作为对照。后肢缺血后，与NTg相比，EWT的血流恢复增强，EDN的血流恢复受损。在EWT中，缺血肌肉和心脏EC中的血管内皮生长因子受体2（VEGFR2）、内皮型一氧化氮合酶（eNOS）和转化生长因子β 1（TGF β 1）的关键血管生成调节基因均上调，而在EDN EC中TGF β 1下调。在EC中，VEGFA和TGF β 1均刺激EWT的EC增殖、迁移和毛细血管样网络形成，但在EDN中未能做到这一点。应用TGF β 1增加VEGFR2和eNOS表达水平，而阻断TGF β 1或加入过氧化氢酶抑制VEGFR2和eNOS的磷酸化，表明Nox 4下游的H2O2和TGF β 1信号传导对维持EC血管生成功能至关重要。使用具有内皮Nox 4的上调和下调的细胞特异性转基因小鼠表明与Nox 4相关的几种机制在血管生成中起作用。内皮Nox4可能通过H2O2和TGF β 1介导的内皮功能所必需的细胞信号通路的激活来调节缺血诱导的血管生成。(C)2014爱思唯尔有限公司版权所有。
Vascular endothelial cells (ECs) are responsible for post-ischemic angiogenesis, a process that is regulated by reactive oxygen species. Recent studies indicate that endothelial Nox4 based NADPH oxidase may have a key role. This study examines the role of endothelial Nox4 in ischemia-induced angiogenesis and explores the potential mechanisms involved. Mouse lines overexpressing human Nox4 wild type (EWT) or its dominant negative form P437H (EDN) specifically in the endothelium were used. Non-transgenic littermate mice (NTg) were used as controls. Following hind limb ischemia, blood flow recovery was enhanced in EWT and was impaired in EDN compared with NTg. The critical angiogenesis regulating genes vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and transforming growth factor beta 1 (TGF beta 1) were upregulated in EWT both in the ischemic muscle and in heart ECs, while TGF beta 1 was downregulated in EDN ECs. In EC, both VEGFA and TGF beta 1 stimulated EC proliferation, migration, and capillary-like network formation in EWT but failed to do so in EDN. Application of TGF beta 1 increased both VEGFR2 and eNOS expression levels, whereas blocking TGF beta 1 or addition of catalase inhibited the phosphorylation of VEGFR2 and eNOS, indicating H2O2 and TGF beta 1 signaling downstream of Nox4 is critical to maintain EC angiogenic functions. Use of cell specific transgenic mice with both upregulation and downregulation of endothelial Nox4 indicate several mechanisms linked to Nox4 play a role in angiogenesis. Endothelial Nox4 regulates ischemia-induced angiogenesis, likely through H2O2- and TGF beta 1-mediated activation of cell signaling pathways essential for endothelial function. (C) 2014 Elsevier B.V. All rights reserved.