College of Pharmacy, Ajou University, San 5, Woncheon-Dong, Yeongtong-Gu, Suwon 443-749, Republic of Korea.
Biochem Biophys Res Commun. 2012 Mar 9;419(2):281-6. doi: 10.1016/j.bbrc.2012.02.009. Epub 2012 Feb 10.
Although Angiopoietin (Ang) 2 has been shown to function as a Tie2 antagonist in vascular endothelial cells, several recent studies on Ang2-deficient mice have reported that, like Ang1, Ang2 acts as a Tie2 agonist during in vivo lymphangiogenesis. However, the mechanism governing the Tie2 agonistic activity of Ang2 in lymphatic endothelial cells has not been investigated. We found that both Ang1 and Ang2 enhanced the in vitro angiogenic and anti-apoptotic activities of human lymphatic endothelial cells (HLECs) through the Tie2/Akt signaling pathway, while only Ang1 elicited such effects in human umbilical vein vascular endothelial cells (HUVECs). This Tie2-agonistic effect of Ang2 in HLECs resulted from low levels of physical association between Tie2 and Tie1 receptors due to a reduced level of Tie1 expression in HLECs compared to HUVECs. Overexpression of Tie1 and the resulting increase in formation of Tie1/Tie2 heterocomplexes in HLECs completely abolished Ang2-mediated Tie2 activation and the subsequent cellular responses, but did not alter the Ang1 function. This inhibitory role of Tie1 in Ang2-induced Tie2 activation was also confirmed in non-endothelial cells with adenovirus-mediated ectopic expression of Tie1 and/or Tie2. To our knowledge, this study is the first to describe how Ang2 acts as a Tie2 agonist in HLECs. Our results suggest that the expression level of Tie1 and its physical interaction with Tie2 defines whether Ang2 functions as a Tie2 agonist or antagonist, thereby determining the context-dependent differential endothelial sensitivity to Ang2.
虽然血管生成素（Ang）2 已被证明在血管内皮细胞中作为 Tie2 的拮抗剂发挥作用，但最近几项关于 Ang2 缺陷小鼠的研究报告称，与 Ang1 一样，Ang2 在体内淋巴管生成过程中作为 Tie2 的激动剂发挥作用。然而，Ang2 在淋巴管内皮细胞中作为 Tie2 激动剂的作用机制尚未得到研究。我们发现，Ang1 和 Ang2 均可通过 Tie2/Akt 信号通路增强人淋巴管内皮细胞（HLEC）的体外血管生成和抗凋亡活性，而 Ang1 仅在人脐静脉血管内皮细胞（HUVEC）中产生这种作用。与 HUVEC 相比，HLEC 中 Tie1 表达水平降低，导致 Tie2 和 Tie1 受体之间的物理结合水平降低，从而导致 Ang2 在 HLEC 中产生 Tie2 激动作用。HLEC 中 Tie1 的过表达及其导致的 Tie1/Tie2 异源二聚体形成增加，完全消除了 Ang2 介导的 Tie2 激活和随后的细胞反应，但不改变 Ang1 的功能。在非内皮细胞中，通过腺病毒介导的 Tie1 和/或 Tie2 异位表达，也证实了 Tie1 在 Ang2 诱导的 Tie2 激活中的抑制作用。据我们所知，这项研究首次描述了 Ang2 如何在 HLEC 中作为 Tie2 激动剂发挥作用。我们的结果表明，Tie1 的表达水平及其与 Tie2 的物理相互作用决定了 Ang2 是作为 Tie2 激动剂还是拮抗剂发挥作用，从而决定了 Ang2 对内皮细胞的上下文依赖性差异敏感性。
