Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway
Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway
复制标题
DOI：
10.1016/j.yexcr.2004.04.013
复制
发表时间：
2004-08-01
影响因子：
3.7
通讯作者：
Lin, PC
中科院分区：
文献类型：
--
作者：
DeBusk, LM;Hallahan, DE;Lin, PC
Tie2和血管内皮生长因子受体(VEGFRs)是酪氨酸激酶，在血管生成中发挥重要作用。这两种受体的激活都会导致Akt的激活，Akt是细胞存活和运动的重要介质。在这项研究中，我们比较了Akt在Tie2和VEGF介导的内皮细胞(EC)存活和EC萌发中的作用。我们的数据表明，Akt是必需的，并且足以介导Ang1诱导的EC在生长因子耗尽时的存活。阻断Akt功能可取消血管生成素1(Ang1)，血管生成素1(Ang1)是Tie2的配体，介导EC存活，激活Akt可挽救Tie2阻断诱导的EC凋亡。相反，激活Akt可以挽救由VEGF阻断诱导的EC的凋亡，但有趣的是，阻断Akt功能对VEGF诱导的EC存活没有影响，这表明Akt对于VEGF介导的EC存活是充分的，但不是必需的。此外，我们还发现，Ang1和VEGF都能诱导EC在三维胶原凝胶中萌发，这依赖于Akt的激活。阻断Akt的作用可抑制Ang1或VEGF诱导的EC萌发。因此，本研究结果表明Akt是Ang1诱导EC存活的主要调节因子，而VEGF下游多条通路参与了EC存活。然而，Akt是介导Ang1和VEGF诱导的EC萌发所必需的，并且是足够的。(C)2004 Elsevier Inc.保留所有权利。
Tie2 and VEGF receptors (VEGFRs) are tyrosine kinases that play essential roles in angiogenesis. Activation of both receptors leads to the activation of Akt, an important mediator of cell survival and cell motility. In this study, we compared the role of Akt in Tie2-mediated versus VEGF-mediated endothelial cell (EC) survival and EC sprouting. Our data show that Akt is required and sufficient to mediate Ang1-induced EC survival in response to growth factor depletion. Blocking Akt function abolishes angiopoietin 1 (Ang1), a ligand for Tie2, mediated EC survival, and activating Akt rescues a Tie2 blockade-induced EC apoptosis. In contrast, activating Akt rescues EC apoptosis induced by a VEGF blockade, but interestingly, blocking Akt function has no effects on VEGF-induced EC survival, demonstrating that Akt is sufficient but not required for VEGF-mediated EC survival. In addition, we show that both Ang1 and VEGF induce EC sprouting in a three-dimensional collagen gel, which depends on the activation of Akt. Blocking Akt action inhibited EC sprouting induced by Ang1 or VEGF. Therefore, the data show that Akt is the primary mediator of Ang1-induced EC survival while multiple pathways are involved downstream of VEGF responsible for EC survival. However, Akt is required and sufficient to mediate the EC sprouting induced by both Ang1 and VEGF. (C) 2004 Elsevier Inc. All rights reserved.