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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells
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Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells

机译：血管生成素2在压力内皮细胞中起自分泌保护因子的作用

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摘要

Angiopoietin (Ang)-2, a context-dependent agonist/antagonist for the vascular-specific Tie2 receptor, is highly expressed by endothelial cells at sites of normal and pathologic angiogenesis. One prevailing model suggests that in these settings, Ang-2 acts as an autocrine Tie2 blocker, inhibiting the stabilizing influence of the Tie2 activator Ang-1, thereby promoting vascular remodeling. However, the effects of endogenous Ang-2 on cells that are actively producing it have not been studied in detail. Here, we demonstrate that Ang-2 expression is rapidly induced in endothelial cells by the transcription factor FOXO1 after inhibition of the phosphatidylinositol 3-kinase/Akt pathway. We employ RNAi and blocking antibodies to show that in this setting, Ang-2 unexpectedly functions as a Tie2 agonist, bolstering Akt activity so as to provide negative feedback on FOXO1-regulated transcription and apoptosis. In addition, we show that Ang-2, like Ang-1, activates Tie2/Akt signaling in vivo, thereby inhibiting the expression of FOXO1 target genes. Consistent with a role for Ang-2 as a Tie2 activator, we demonstrate that Ang-2 inhibits vascular leak. Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor.
机译：血管生成素（Ang）-2是血管特异性Tie2受体的上下文相关激动剂/拮抗剂，在正常和病理性血管生成部位由内皮细胞高度表达。一种流行的模型表明，在这些情况下，Ang-2可以作为自分泌的Tie2阻断剂，抑制Tie2激活剂Ang-1的稳定作用，从而促进血管重塑。然而，尚未详细研究内源性Ang-2对活跃产生Ang-2的细胞的作用。在这里，我们证明了在抑制磷脂酰肌醇3-激酶/ Akt途径后，转录因子FOXO1在血管内皮细胞中迅速诱导Ang-2表达。我们使用RNAi和封闭抗体来显示在这种情况下，Ang-2意外地充当Tie2激动剂，增强Akt活性，从而对FOXO1调控的转录和凋亡提供负反馈。此外，我们显示Ang-2与Ang-1一样，在体内激活Tie2 / Akt信号传导，从而抑制FOXO1靶基因的表达。与Ang-2作为Tie2激活剂的作用一致，我们证明了Ang-2抑制血管渗漏。我们的数据提示了在应激的内皮细胞中诱导Ang-2表达的模型，在该模型中Ang-2表现为自分泌Tie2激动剂和保护因子。

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