Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt
Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt
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DOI：
10.1161/01.res.86.8.892
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发表时间：
2000-04-28
影响因子：
20.1
通讯作者：
Sessa, WC
中科院分区：
文献类型：
--
作者：
Morales-Ruiz, M;Fulton, D;Sessa, WC
血管内皮生长因子（VEGF）诱导内皮细胞增殖、迁移和肌动蛋白重组，这些都是血管生成反应的必要组成部分。然而，导致每种血管生成表型的不同信号转导机制尚不清楚。在这项研究中，我们研究了VEGF刺激细胞迁移和肌动蛋白重排的能力，在微血管内皮细胞感染腺病毒编码β-半乳糖苷酶（β-gal），激活缺陷型Akt（AA-Akt），或组成型活性Akt（myr-Akt）。VEGF增加了β-gal转导的细胞中的细胞迁移，而AA-Akt阻断了VEGF诱导的细胞运动。有趣的是，myr-Akt转导的牛肺微血管内皮细胞刺激胞质分裂在VEGF的情况下，这表明，组成型活性Akt本身，可以启动细胞迁移的过程。用NO合成抑制剂处理β-gal感染的内皮细胞阻断VEGF诱导的迁移，但不影响myr-Akt启动的迁移。此外，VEGF刺激肌动蛋白细胞骨架重塑为应力纤维，显性阴性Akt感染可消除这种反应，而单独用myr-Akt转导可引起F-肌动蛋白的深刻重组。总的来说，这些数据表明，Akt是关键参与内皮细胞信号转导机制，导致迁移和Akt/内皮NO合酶途径是VEGF刺激的细胞迁移所必需的。
Vascular endothelial growth factor (VEGF) induces endothelial cell proliferation, migration, and actin reorganization, ail necessary components of an angiogenic response. However, the distinct signal transduction mechanisms leading to each angiogenic phenotype are not known. In this study, we examined the ability of VEGF to stimulate cell migration and actin rearrangement in microvascular endothelial cells infected with adenoviruses encoding beta-galactosidase (beta-gal), activation-deficient Akt (AA-Akt), or constitutively active Akt (myr-Akt). VEGF increased cell migration in cells transduced with beta-gal, whereas AA-Akt blocked VEGF-induced cell locomotion. Interestingly, myr-Akt transduction of bovine lung microvascular endothelial cells stimulated cytokinesis in the absence of VEGF, suggesting that constitutively active Akt, per se, can initiate the process of cell migration. Treatment of beta-gal-infected endothelial cells with an inhibitor of NO synthesis blocked VEGF-induced migration but did not influence migration initiated by myr-Akt. In addition, VEGF stimulated remodeling of the actin cytoskeleton into stress fibers, a response abrogated by infection with dominant-negative Akt, whereas transduction with myr-Akt alone caused profound reorganization of F-actin. Collectively, these data demonstrate that Akt is critically involved in endothelial cell signal transduction mechanisms leading to migration and that the Akt/endothelial NO synthase pathway is necessary for VEGF-stimulated cell migration.