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Research Articles: Therapeutics, Targets, and Development

Fasudil inhibits vascular endothelial growth factor–induced angiogenesis in vitro and in vivo

¹ Department of Obstetrics and Gynecology, Yamagata University, School of Medicine, Yamagata, Japan and ² Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan

Requests for reprints: Ken-ichirou Morishige, Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3354; Fax: 81-6-6879-3359; E-mail: mken{at}gyne.med.osaka-u.ac.jp

Abstract

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. [Mol Cancer Ther 2007;6(5):1517–25]

Grant support: Grants-in-Aid for Scientific Research nos. 14370523 (H. Kurachi) and 18591822 (K. Takahashi) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and in part by Grants-in-Aid for the 21st Century Center of Excellence Program from the Japan Society for the Promotion of Science.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 9/06; revised 2/27/07; accepted 3/23/07.

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