Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation
Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation
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DOI：
10.1038/nm1351
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发表时间：
2006-02-01
期刊：
影响因子：
82.9
通讯作者：
Augustin, HG
中科院分区：
文献类型：
--
作者：
Fiedler, U;Reiss, Y;Augustin, HG
血管生成素Ang-1和Ang-2已被鉴定为受体酪氨酸激酶Tie-2的配体（参考文献11）。1、2）。旁分泌Ang-1介导的Tie-2活化可作为血管成熟和血管静止的调节剂（3，4）。反过来，拮抗性配体Ang-2通过自分泌机制起作用（5-7），并储存在内皮韦伯-帕拉德体中，在刺激时可迅速释放（8）。Ang-2的快速释放意味着血管生成素-Tie系统的功能超出了其在血管形态发生期间作为快速血管反应的调节剂的既定作用。在这里，我们表明，小鼠缺乏血管紧张素-2（Angpt 2基因编码）不能引起巯基乙酸盐诱导或金黄色葡萄球菌诱导的腹膜炎，或在背皮褶腔模型的炎症反应。重组Ang-2修复Angpt 2（-/-）小鼠的炎症缺陷。活体显微镜检查显示Angpt 2（-/-）小鼠血管中正常的TNF-α诱导的白细胞滚动，但滚动细胞不能牢固地粘附于活化的内皮。细胞实验表明，Ang-2通过使内皮细胞对TNF-α敏感并调节TNF-α诱导的内皮细胞粘附分子的表达来促进粘附。总之，这些发现确定血管紧张素-2作为自分泌调节内皮细胞炎症反应。因此，Ang-2作为血管反应性的开关，对促炎细胞因子的活性发挥允许作用。
The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence(3,4). In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism(5-7) and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation(8). The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-) mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.