Fasudil inhibits vascular endothelial growth factor -: induced angiogenesis in vitro and in vivo
Fasudil inhibits vascular endothelial growth factor -: induced angiogenesis in vitro and in vivo
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DOI：
10.1158/1535-7163.mct-06-0689
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发表时间：
2007-05-01
影响因子：
5.7
通讯作者：
Kurachi, Hirohisa
中科院分区：
文献类型：
--
作者：
Yin, Limei;Morishige, Ken-ichirou;Kurachi, Hirohisa
血管内皮生长因子（VEGF）诱导的内皮细胞迁移是肿瘤血管生成的重要组成部分。Rho和Rho相关激酶（ROCK）是粘着斑、应力纤维形成和细胞运动的关键调节因子。该途径的抑制剂已显示抑制内皮细胞运动和血管生成。在这项研究中，我们研究了ROCK抑制剂之一法舒地尔的抗血管生成作用。法舒地尔在体外抑制VEGF诱导的人脐静脉内皮细胞迁移、活力和管形成。VEGF诱导的内皮细胞迁移减少法舒地尔与损失的应力纤维形成，粘着斑组装，并与抑制酪氨酸磷酸化的粘着斑蛋白。此外，法舒地尔抑制VEGF诱导的肌球蛋白轻链磷酸化，这是ROCK的主要底物之一。因此，法舒地尔的作用具有ROCK依赖性。法舒地尔不仅抑制VEGF诱导的细胞增殖，而且逆转VEGF对细胞凋亡的保护作用，导致细胞活力下降。此外，法舒地尔在定向体内血管生成测定中抑制VEGF诱导的血管生成。这些数据首次证明法舒地尔具有抗血管生成特性。因此，法舒地尔可能用于治疗血管生成相关疾病，特别是癌症。
Vascular endothelial growth factor (VEGF)-induced endothelial cell migration is an important component of tumor angiogenesis. Rho and Rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber formation, and thus cell motility. Inhibitors of this pathway have been shown to inhibit endothelial cell motility and angiogenesis. In this study, we investigated the antiangiogenic effect of fasudil, one of the ROCK inhibitors. Fasudil inhibited VEGF-induced endothelial cell migration, viability, and tube formation in vitro in human umbilical vein endothelial cells. VEGF-induced endothelial cell migration was reduced by fasudil associated with loss of stress fiber formation, focal adhesion assembly, and with the suppression of tyrosine phosphorylation of focal adhesion proteins. Furthermore, fasudil inhibited VEGF-induced phosphorylation of myosin light chain, which is one of the main substrates of ROCK. Therefore, the effect of fasudil was suggested to be ROCK dependent. Fasudil not only inhibited VEGF-induced cell proliferation but also reversed the protective effect of VEGF on apoptosis, which resulted in the decrease of cell viability. Moreover, fasudil inhibited VEGF-induced angiogenesis in a directed in vivo angiogenesis assay. These data are the first demonstration that fasudil has antiangiogenic properties. Therefore, fasudil might be useful for the treatment of angiogenesis-related diseases, especially cancer.