Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT
Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT
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DOI：
10.1038/386403a0
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发表时间：
1997-03-27
期刊：
影响因子：
64.8
通讯作者：
Simon, MC
中科院分区：
文献类型：
--
作者：
Maltepe, E;Schmidt, JV;Simon, MC
芳烃受体核转位蛋白（ARNT）是异二聚体转录因子的碱性螺旋环螺旋PAS家族的成员，该家族包括芳烃受体（AHR）、缺氧诱导因子-1 α（HIF-1 α）、（HIF-1 α）和果蝇专一蛋白（Sim）（1-4），ARNT与芳香烃受体、HIF-1 α、Sim和PAS蛋白Per形成异二聚体复合物（2，（第4至6段）。在对环境污染物的反应中，AHR-ARNT异二聚体调节参与外源性物质代谢的基因（7-9），而ARNT-HIF-1 α异二聚体可能调节参与对缺氧反应的基因（10-13）。通过在小鼠中产生Arnt位点的靶向破坏，我们在这里显示Arnt（-/-）胚胎干细胞不能激活通常对低氧张力响应的基因，Arnt（-/-）ES细胞也不能对葡萄糖浓度的降低响应，这表明ARNT在对缺氧和低血糖的响应中至关重要。Arnt（-/-）胚胎在胚胎10.5天后不能存活，并且显示卵黄囊和鳃弓的血管生成缺陷、发育迟缓和胚胎萎缩。Arnt（-/-）卵黄囊中血管形成的缺陷类似于对缺乏血管内皮生长因子（14，15）或组织因子（16）的小鼠报道的血管生成异常。在这些发现的基础上，我们提出了一个模型，在器官形成过程中增加组织质量导致缺氧/营养缺乏细胞的形成，随后激活ARNT，并伴随着基因表达的增加（包括编码血管内皮生长因子），促进血管化的发展卵黄囊和实体组织。
The arylhydrocarbon-receptor nuclear translocator (ARNT) is a member of the basic-helix-loop-helix-PAS family of heterodimeric transcription factors which includes the arylhydrocarbon receptor (AHR), hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the Drosophila single-minded protein (Sim)(1-4), ARNT forms heterodimeric complexes with the arylhydrocarbon receptor, HIF-1 alpha, Sim and the PAS protein Per(2,4-6). In response to environmental pollutants, AHR-ARNT heterodimers regulate genes involved in the metabolism of xenobiotics(7-9), whereas ARNT-HIF-1 alpha heterodimers probably regulate those involved in the response to oxygen deprivation(10-13). By generating a targeted disruption of the Arnt locus in the mouse, we show here that Arnt(-/-) embryonic stem cells fail to activate genes that normally respond to low oxygen tension, Arnt(-/-) ES cells also failed to respond to a decrease in glucose concentration, indicating that ARNT is crucial in the response to hypoxia and to hypoglycaemia. Arnt(-/-) embryos were not viable past embryonic day 10.5 and showed defective angiogenesis of the yolk sac and branchial arches, stunted development and embryo wasting, The defect in blood vessel formation in Arnt(-/-) yolk sacs is similar to the angiogenic abnormalities reported for mice deficient in vascular endothelial growth factor(14,15) or tissue factor(16). On the basis of these findings, we propose a model in which increasing tissue mass during organogenesis leads to the formation of hyoxic/nutrient-deprived cells, the subsequent activation of ARNT, and a concomitant increase in the expression of genes (including that encoding vascular endothelial growth factor) that promote vascularization of the developing yolk sac and solid tissues.