Cyclin-dependent Kinase 5 Regulates Endothelial Cell Migration and Angiogenesis
Cyclin-dependent Kinase 5 Regulates Endothelial Cell Migration and Angiogenesis
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DOI：
10.1074/jbc.m110.126177
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发表时间：
2010-11-12
影响因子：
4.8
通讯作者：
Zahler, Stefan
中科院分区：
文献类型：
--
作者：
Liebl, Johanna;Weitensteiner, Sabine B.;Zahler, Stefan
血管生成有助于各种病理条件。由于对现有抗血管生成治疗的耐药性，迫切需要了解血管生长的分子基础并确定抗血管生成治疗的新靶点。在这里，我们发现细胞周期蛋白依赖性激酶5 (Cdk5)，一个重要的神经元过程调节剂，调节内皮细胞迁移和血管生成，提示Cdk5作为抗血管生成治疗的新靶点。在体外和体内，抑制或敲低Cdk5可降低内皮细胞的运动性并阻断血管生成。我们阐明了Cdk5在内皮细胞中的特异性信号传导；与神经元细胞相反，Cdk5抑制后的运动缺陷不是由局灶粘连或微管功能受损引起的，而是由板足形成减少引起的。抑制或下调Cdk5降低小GTPase Rac1的活性，导致肌动蛋白细胞骨架紊乱。组成型活性Rac1补偿了Cdk5敲低对迁移的抑制作用，表明Cdk5通过Rac1在内皮细胞迁移中发挥作用。我们的工作阐明了Cdk5作为内皮细胞迁移和血管生成的关键新调节剂。这表明Cdk5是一种新的、药理学上可及的抗血管生成治疗靶点，并为Cdk5抑制剂作为抗血管生成药物的新治疗应用提供了基础。
Angiogenesis contributes to various pathological conditions. Due to the resistance against existing antiangiogenic therapy, an urgent need exists to understand the molecular basis of vessel growth and to identify new targets for antiangiogenic therapy. Here we show that cyclin-dependent kinase 5 (Cdk5), an important modulator of neuronal processes, regulates endothelial cell migration and angiogenesis, suggesting Cdk5 as a novel target for antiangiogenic therapy. Inhibition or knockdown of Cdk5 reduces endothelial cell motility and blocks angiogenesis in vitro and in vivo. We elucidate a specific signaling of Cdk5 in the endothelium; in contrast to neuronal cells, the motile defects upon inhibition of Cdk5 are not caused by an impaired function of focal adhesions or microtubules but by the reduced formation of lamellipodia. Inhibition or down-regulation of Cdk5 decreases the activity of the small GTPase Rac1 and results in a disorganized actin cytoskeleton. Constitutive active Rac1 compensates for the inhibiting effects of Cdk5 knockdown on migration, suggesting that Cdk5 exerts its effects in endothelial cell migration via Rac1. Our work elucidates Cdk5 as a pivotal new regulator of endothelial cell migration and angiogenesis. It suggests Cdk5 as a novel, pharmacologically accessible target for antiangiogenic therapy and provides the basis for a new therapeutic application of Cdk5 inhibitors as antiangiogenic agents.