HIF-2α is essential for carotid body development and function
HIF-2α is essential for carotid body development and function
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DOI：
10.7554/elife.34681
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发表时间：
2018-04-19
期刊：
影响因子：
7.7
通讯作者：
Johnson, Randall S.
中科院分区：
文献类型：
--
作者：
Macias, David;Cowburn, Andrew S.;Johnson, Randall S.
哺乳动物对氧通量的适应发生在许多水平，从细胞代谢的转变到由交感神经系统和颈动脉体（CB）促进的生理适应。不同形式的低氧适应性反应之间的相互作用，包括由低氧诱导转录因子（HIF）协调的转录反应，是复杂的，明显协同。我们在这里表明，有一个绝对的发展需要HIF-2 α，HIF亚型之一，生长和生存的氧敏感性血管球细胞的颈动脉体。这些细胞的丧失使小鼠不能对缺氧作出反应，这对动脉压调节、运动表现和葡萄糖稳态等多种过程具有显著影响。我们发现，球细胞的扩增与mTORC 1激活相关，并在功能上受到雷帕霉素治疗的抑制。这些发现证明了HIF-2 α在颈动脉体发育、生长和功能中发挥的核心作用。
Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2 alpha, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2 alpha in carotid body development, growth and function.