Tie1 controls angiopoietin function in vascular remodeling and inflammation
Tie1 controls angiopoietin function in vascular remodeling and inflammation
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DOI：
10.1172/jci84923
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Saharinen, Pipsa
中科院分区：
文献类型：
--
作者：
Korhonen, Emilia A.;Lampinen, Anita;Saharinen, Pipsa
血管生成素/Tie(Ang/Tie)受体系统控制发育和肿瘤血管生成、炎性血管重塑和血管渗漏。Ang1是一种Tie2激动剂，在炎症和脓毒症中促进血管稳定，而ANG2是上下文依赖的Tie2激动剂或拮抗剂。对Ang信号转导机制和孤儿受体Tie1的有限了解阻碍了Ang/Tie靶向治疗的发展。在这里，我们确定了Ang1和ANG2与Tie2的结合都以131整合素依赖的方式增加了Tie1-Tie2的相互作用，并且Tie1调节Ang诱导的Tie2在内皮细胞中的运输。内皮细胞Tie1对血管紧张素转换酶1和自分泌血管紧张素转换酶2的激活作用是必不可少的。小鼠内皮细胞Tiel的缺失减少了Tie2的磷酸化和下游Akt的激活，增加了FOXO1的核定位和转录激活，并阻止了Ang1和ANG2诱导的毛细血管到静脉重构。然而，在急性内毒素血症中，负责与Tie2相互作用的Tie1胞外区被迅速切割，Ang1激动剂活性降低，自分泌ANG2激动剂活性丧失，导致Tie2信号被抑制。在感染汉坦病毒的患者中也出现了Tie1裂解。这些结果支持这样一个模型，即在非炎症条件下，Tie1与Tie2直接相互作用以促进Ang诱导的血管反应，而在炎症条件下，Tie1裂解导致ANG2激动剂活性和血管稳定性的丧失。
The angiopoietin/Tie (ANG/Tie) receptor system controls developmental and tumor angiogenesis, inflammatory vascular remodeling, and vessel leakage. ANG1 is a Tie2 agonist that promotes vascular stabilization in inflammation and sepsis, whereas ANG2 is a context-dependent Tie2 agonist or antagonist. A limited understanding of ANG signaling mechanisms and the orphan receptor Tie1 has hindered development of ANG/Tie-targeted therapeutics. Here, we determined that both ANG1 and ANG2 binding to Tie2 increases Tie1-Tie2 interactions in a 131 integrin-dependent manner and that Tie1 regulates ANG-induced Tie2 trafficking in endothelial cells. Endothelial Tie1 was essential for the agonist activity of ANG1 and autocrine ANG2. Deletion of endothelial Tiel in mice reduced Tie2 phosphorylation and downstream Akt activation, increased FOXO1 nuclear localization and transcriptional activation, and prevented ANG1- and ANG2-induced capillary-to-venous remodeling. However, in acute endotoxemia, the Tie1 ectodomain that is responsible for interaction with Tie2 was rapidly cleaved, ANG1 agonist activity was decreased, and autocrine ANG2 agonist activity was lost, which led to suppression of Tie2 signaling. Tie1 cleavage also occurred in patients with hantavirus infection. These results support a model in which Tie1 directly interacts with Tie2 to promote ANG-induced vascular responses under noninflammatory conditions, whereas in inflammation, Tie1 cleavage contributes to loss of ANG2 agonist activity and vascular stability.