Soga N, Namba N, McAllister S, Cornelius L, Teitelbaum S L, Dowdy S F, Kawamura J, Hruska K A
Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Exp Cell Res. 2001 Sep 10;269(1):73-87. doi: 10.1006/excr.2001.5295.
Migration of endothelial cells induced by vascular endothelial growth factor (VEGF) is a critical step in angiogenesis. Stimulation of motility by growth factors such as VEGF requires interaction with the signal transduction pathways activated by the extracellular matrix (ECM). Here we demonstrate that the Rac GTPase is the critical intersection activated by type 1 collagen ECM and VEGF during stimulation of endothelial cell motility. To analyze the role of the Rho family GTPases in VEGF-stimulated endothelial cell chemotaxis and ECM-stimulated haptotaxis, we transduced the respective fusion proteins in human foreskin dermal endothelial cells using a Tat peptide from the human immunodeficiency virus Tat protein. VEGF signaling required Rac activation during chemotaxis, and Rac and Cdc42 were activated during haptotaxis on type I collagen. Similar to VEGF, Rac activation induced an increase in endothelial cell stress fiber and focal adhesion. Surprisingly, Rho activation was not present in collagen-induced haptotaxis or stimulation of chemotaxis by VEGF, although Rho induced stress fibers and focal adhesions similar to Rac activation. The result of constitutive Rho activation was an inhibition of haptotaxis. Thus, Rac is required and sufficient for the activation of endothelial cell haptotaxis and VEGF-stimulated chemotaxis.
血管内皮生长因子（VEGF）诱导的内皮细胞迁移是血管生成中的关键步骤。诸如VEGF等生长因子对运动性的刺激需要与细胞外基质（ECM）激活的信号转导途径相互作用。在此我们证明，在刺激内皮细胞运动期间，Rac GTP酶是由I型胶原ECM和VEGF激活的关键交汇点。为了分析Rho家族GTP酶在VEGF刺激的内皮细胞趋化性和ECM刺激的趋触性中的作用，我们使用来自人类免疫缺陷病毒Tat蛋白的Tat肽在人包皮真皮内皮细胞中转导各自的融合蛋白。VEGF信号传导在趋化性期间需要Rac激活，并且在I型胶原上的趋触性期间Rac和Cdc42被激活。与VEGF相似，Rac激活诱导内皮细胞应力纤维和粘着斑增加。令人惊讶的是，在胶原诱导的趋触性或VEGF刺激的趋化性中不存在Rho激活，尽管Rho诱导的应力纤维和粘着斑与Rac激活相似。组成型Rho激活的结果是趋触性受到抑制。因此，Rac对于激活内皮细胞趋触性和VEGF刺激的趋化性是必需的且足够的。
