Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation
Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation
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DOI：
10.1172/jci84871
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
McDonald, Donald M.
中科院分区：
文献类型：
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作者：
Kim, Minah;Allen, Breanna;McDonald, Donald M.
血管生成素-2（Angiopoietin-2，ANG 2）通过对Tie 2信号传导的不同作用调节许多病理条件下的血管重塑。虽然ANG 2与ANG 1竞争抑制Tie 2，但它也可以促进Tie 2磷酸化（p-Tie 2）。一个相关的矛盾是Tie 2的失活和过度活化都可能导致血管重塑。在这里，我们通过操纵控制其在脉管系统中的作用的条件来调和ANG 2的这些相反的作用。在肺支原体感染期间，ANG 2通过作为Tie 2拮抗剂驱动血管重塑，这导致p-Tie 2抑制、叉头框01（FOXO 1）激活、ANG 2表达增加和血管渗漏。这些变化被抗Tie 2抗体、PI 3 K信号传导抑制或ANG 2过表达放大，并被抗ANG 2抗体或外源性ANG 1降低。相比之下，在无病原体的条件下，ANG 2通过作为激动剂，促进高p-Tie 2，低FOX 01活化和无渗漏来驱动血管重塑。在无病原体条件下，Tie 1激活很强，但感染或TNF-α导致Tie 1通过胞外域切割失活，并促进ANG 2的Tie 2拮抗剂作用。总之，这些数据表明，Tie 2的ANG 2激活支持正常无渗漏血管的稳定扩张，但炎症中Tie 1的减少导致ANG 2拮抗Tie 2并启动正反馈回路，其中FOXO 1驱动的ANG 2表达促进血管重塑和渗漏。
Angiopoietin-2 (ANG2) regulates blood vessel remodeling in many pathological conditions through differential effects on Tie2 signaling. While ANG2 competes with ANG1 to inhibit Tie2, it can paradoxically also promote Tie2 phosphorylation (p-Tie2). A related paradox is that both inactivation and overactivation of Tie2 can result in vascular remodeling. Here, we reconciled these opposing actions of ANG2 by manipulating conditions that govern its actions in the vasculature. ANG2 drove vascular remodeling during Mycoplasma pulmonis infection by acting as a Tie2 antagonist, which led to p-Tie2 suppression, forkhead box 01 (FOXO1) activation, increased ANG2 expression, and vessel leakiness. These changes were exaggerated by anti Tie2 antibody, inhibition of PI3K(signaling, or ANG2 overexpression and were reduced by anti-ANG2 antibody or exogenous ANG1. In contrast, under pathogen-free conditions, ANG2 drove vascular remodeling by acting as an agonist, promoting high p-Tie2, low FOX01 activation, and no leakage. Tie1 activation was strong under pathogen-free conditions, but infection or TNF-alpha led to Tie1 inactivation by ectodomain cleavage and promoted the Tie2 antagonist action of ANG2. Together, these data indicate that ANG2 activation of Tie2 supports stable enlargement of normal nonleaky vessels, but reduction of Tie1 in inflammation leads to ANG2 antagonism of Tie2 and initiates a positive feedback loop Wherein FOXO1-driven ANG2 expression promotes vascular remodeling and leakage.