Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia.
Inhibition of ARNT severely compromises endothelial cell viability and function in response to moderate hypoxia.
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DOI：
10.1007/s10456-012-9269-x
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发表时间：
2012-09
期刊：
影响因子：
9.8
通讯作者：
Ramirez-Bergeron, Diana L.
中科院分区：
文献类型：
--
作者：
Han, Yu;Yang, Ke;Proweller, Aaron;Zhou, Guangjin;Jain, Mukesh K.;Ramirez-Bergeron, Diana L.
缺氧诱导因子（HIF）是一种主要的异二聚体氧（O2）稳态转录调节因子，对适当的血管生成反应至关重要。由于内皮细胞中HIF-1α和HIF-2α亚基的独特共表达，我们的目标是通过使用HIF-β亚基（ARNT，芳基烃受体核转运子）减少HIF转录反应所需的遗传模型，研究在生理缺氧条件下HIF转录活性的遗传消除。从ArntloxP/loxP小鼠中分离内皮细胞（ECs）和主动脉外植体，用-Cre/GFP腺病毒或对照-GFP感染。我们观察到，在对照主动脉环试验中，2.5%的O2水平促进了血管的发芽、生长和分支，而腺病毒-Cre感染的外植体的生长受到抑制。原代腺病毒-Cre感染的EC培养具有不良的迁移和管状形成表型。原发性肺或心脏arnt缺失的ECs在8%或2.5% O2和过氧化氢治疗下也不能增殖和存活。我们的数据表明，ARNT促进EC迁移和血管生长，对于EC在缺氧生理环境提示下的增殖和保存是必不可少的。因此，这些结果表明，ARNT在ECs中起着关键的内在作用，并支持HIF-1和HIF-2在这些细胞中的转录活性协同发挥关键作用。
Hypoxia Inducible Factor (HIF) is a master heterodimeric transcriptional regulator of oxygen (O2) homeostasis critical to proper angiogenic responses. Due to the distinctive coexpression of HIF-1α and HIF-2α subunits in endothelial cells, our goal was to examine the genetic elimination of HIF transcriptional activity in response to physiological hypoxic conditions by using a genetic model in which the required HIF-β subunit (ARNT, Aryl hydrocarbon Receptor Nuclear Translocator) to HIF transcriptional responses was depleted. Endothelial cells (ECs) and aortic explants were isolated from ArntloxP/loxP mice and infected with Adenovirus -Cre/GFP or control -GFP. We observed that moderate levels of 2.5% O2 promoted vessel sprouting, growth, and branching in control aortic ring assays while growth from Adenovirus -Cre infected explants was compromised. Primary Adenovirus -Cre infected EC cultures featured adverse migration and tube formation phenotypes. Primary pulmonary or cardiac ARNT-deleted ECs also failed to proliferate and survive in response to 8 or 2.5% O2 and hydrogen peroxide treatment. Our data demonstrates that ARNT promotes EC migration and vessel outgrowth and indispensible for the proliferation and preservation of ECs in response to the physiological environmental cue of hypoxia. Thus, these results demonstrate that ARNT plays a critical intrinsic role in ECs and support a critical role for the collaboration of HIF-1 and HIF-2 transcriptional activity in these cells.
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