Antiangiogenic properties of fasudil, a potent Rho-kinase inhibitor

Yasuaki Hata, Muneki Miura, shintaro nakao, Shuhei Kawahara, Takeshi Kita, Tatsuro Ishibashi

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Purpose: Vascular endothelial growth factor (VEGF) plays a pivotal role in pathological angiogenesis. In this study, we addressed the therapeutic potential of fasudil, a potent Rho-kinase inhibitor, for VEGF-elicited angiogenesis and also for the intracellular signalings induced by VEGF. Methods: In vitro, the inhibitory effects of fasudil on the VEGF-dependent VEGF receptor 2 (VEFGR2 or KDR), extracellular signal-related kinase (ERK) 1/2, Akt and myosin light chain (MLC) phosphorylation, as well as on the migration and proliferation of bovine retinal microvascular endothelial cells (BRECs) were analyzed with Western blotting, [3H]-thymidine uptake, and modified Boyden chamber assay. VEGF-elicited in vivo angiogenesis was analyzed with a mouse corneal micropocket assay coembedded with or without fasudil. Results: VEGF caused enhanced MLC phosphorylation of BRECs, which was almost completely attenuated by 10μM fasudil. VEGF-dependent phosphorylation of ERK1/2 and Akt were also partially but significantly attenuated by treatment with fasudil without affecting VEGFR2 (KDR) phosphorylation. Moreover, both VEGF-induced [3H]-thymidine uptake and the migration of BRECs were significantly inhibited in the presence of fasudil. Finally, VEGF-elicited angiogenesis in the corneal micropocket assay was potently attenuated by coembedding with fasudil (P < 0.01). Conclusions: These findings indicate that fasudil might have a therapeutic potential for ocular angiogenic diseases. The antiangiogenic effect of fasudil appears to be mediated through the blockade not only of Rho-kinase signaling but also of ERK and Akt signaling.

Original languageEnglish
Pages (from-to)16-23
Number of pages8
JournalJapanese Journal of Ophthalmology
Volume52
Issue number1
DOIs
Publication statusPublished - Feb 1 2008

Fingerprint

rho-Associated Kinases
Vascular Endothelial Growth Factor A
Phosphorylation
Endothelial Cells
Thymidine
Phosphotransferases
Pathologic Neovascularization
Corneal Neovascularization
fasudil
Vascular Endothelial Growth Factor Receptor-2
Myosin Light Chains
Eye Diseases
Western Blotting

All Science Journal Classification (ASJC) codes

  • Ophthalmology

Cite this

Antiangiogenic properties of fasudil, a potent Rho-kinase inhibitor. / Hata, Yasuaki; Miura, Muneki; nakao, shintaro; Kawahara, Shuhei; Kita, Takeshi; Ishibashi, Tatsuro.

In: Japanese Journal of Ophthalmology, Vol. 52, No. 1, 01.02.2008, p. 16-23.

Research output: Contribution to journalArticle

Hata, Yasuaki ; Miura, Muneki ; nakao, shintaro ; Kawahara, Shuhei ; Kita, Takeshi ; Ishibashi, Tatsuro. / Antiangiogenic properties of fasudil, a potent Rho-kinase inhibitor. In: Japanese Journal of Ophthalmology. 2008 ; Vol. 52, No. 1. pp. 16-23.
@article{8c0f6febf3004400bf8b1eef798ae038,
title = "Antiangiogenic properties of fasudil, a potent Rho-kinase inhibitor",
abstract = "Purpose: Vascular endothelial growth factor (VEGF) plays a pivotal role in pathological angiogenesis. In this study, we addressed the therapeutic potential of fasudil, a potent Rho-kinase inhibitor, for VEGF-elicited angiogenesis and also for the intracellular signalings induced by VEGF. Methods: In vitro, the inhibitory effects of fasudil on the VEGF-dependent VEGF receptor 2 (VEFGR2 or KDR), extracellular signal-related kinase (ERK) 1/2, Akt and myosin light chain (MLC) phosphorylation, as well as on the migration and proliferation of bovine retinal microvascular endothelial cells (BRECs) were analyzed with Western blotting, [3H]-thymidine uptake, and modified Boyden chamber assay. VEGF-elicited in vivo angiogenesis was analyzed with a mouse corneal micropocket assay coembedded with or without fasudil. Results: VEGF caused enhanced MLC phosphorylation of BRECs, which was almost completely attenuated by 10μM fasudil. VEGF-dependent phosphorylation of ERK1/2 and Akt were also partially but significantly attenuated by treatment with fasudil without affecting VEGFR2 (KDR) phosphorylation. Moreover, both VEGF-induced [3H]-thymidine uptake and the migration of BRECs were significantly inhibited in the presence of fasudil. Finally, VEGF-elicited angiogenesis in the corneal micropocket assay was potently attenuated by coembedding with fasudil (P < 0.01). Conclusions: These findings indicate that fasudil might have a therapeutic potential for ocular angiogenic diseases. The antiangiogenic effect of fasudil appears to be mediated through the blockade not only of Rho-kinase signaling but also of ERK and Akt signaling.",
author = "Yasuaki Hata and Muneki Miura and shintaro nakao and Shuhei Kawahara and Takeshi Kita and Tatsuro Ishibashi",
year = "2008",
month = "2",
day = "1",
doi = "10.1007/s10384-007-0487-5",
language = "English",
volume = "52",
pages = "16--23",
journal = "Japanese Journal of Ophthalmology",
issn = "0021-5155",
publisher = "Springer Japan",
number = "1",

}

TY - JOUR

T1 - Antiangiogenic properties of fasudil, a potent Rho-kinase inhibitor

AU - Hata, Yasuaki

AU - Miura, Muneki

AU - nakao, shintaro

AU - Kawahara, Shuhei

AU - Kita, Takeshi

AU - Ishibashi, Tatsuro

PY - 2008/2/1

Y1 - 2008/2/1

N2 - Purpose: Vascular endothelial growth factor (VEGF) plays a pivotal role in pathological angiogenesis. In this study, we addressed the therapeutic potential of fasudil, a potent Rho-kinase inhibitor, for VEGF-elicited angiogenesis and also for the intracellular signalings induced by VEGF. Methods: In vitro, the inhibitory effects of fasudil on the VEGF-dependent VEGF receptor 2 (VEFGR2 or KDR), extracellular signal-related kinase (ERK) 1/2, Akt and myosin light chain (MLC) phosphorylation, as well as on the migration and proliferation of bovine retinal microvascular endothelial cells (BRECs) were analyzed with Western blotting, [3H]-thymidine uptake, and modified Boyden chamber assay. VEGF-elicited in vivo angiogenesis was analyzed with a mouse corneal micropocket assay coembedded with or without fasudil. Results: VEGF caused enhanced MLC phosphorylation of BRECs, which was almost completely attenuated by 10μM fasudil. VEGF-dependent phosphorylation of ERK1/2 and Akt were also partially but significantly attenuated by treatment with fasudil without affecting VEGFR2 (KDR) phosphorylation. Moreover, both VEGF-induced [3H]-thymidine uptake and the migration of BRECs were significantly inhibited in the presence of fasudil. Finally, VEGF-elicited angiogenesis in the corneal micropocket assay was potently attenuated by coembedding with fasudil (P < 0.01). Conclusions: These findings indicate that fasudil might have a therapeutic potential for ocular angiogenic diseases. The antiangiogenic effect of fasudil appears to be mediated through the blockade not only of Rho-kinase signaling but also of ERK and Akt signaling.

AB - Purpose: Vascular endothelial growth factor (VEGF) plays a pivotal role in pathological angiogenesis. In this study, we addressed the therapeutic potential of fasudil, a potent Rho-kinase inhibitor, for VEGF-elicited angiogenesis and also for the intracellular signalings induced by VEGF. Methods: In vitro, the inhibitory effects of fasudil on the VEGF-dependent VEGF receptor 2 (VEFGR2 or KDR), extracellular signal-related kinase (ERK) 1/2, Akt and myosin light chain (MLC) phosphorylation, as well as on the migration and proliferation of bovine retinal microvascular endothelial cells (BRECs) were analyzed with Western blotting, [3H]-thymidine uptake, and modified Boyden chamber assay. VEGF-elicited in vivo angiogenesis was analyzed with a mouse corneal micropocket assay coembedded with or without fasudil. Results: VEGF caused enhanced MLC phosphorylation of BRECs, which was almost completely attenuated by 10μM fasudil. VEGF-dependent phosphorylation of ERK1/2 and Akt were also partially but significantly attenuated by treatment with fasudil without affecting VEGFR2 (KDR) phosphorylation. Moreover, both VEGF-induced [3H]-thymidine uptake and the migration of BRECs were significantly inhibited in the presence of fasudil. Finally, VEGF-elicited angiogenesis in the corneal micropocket assay was potently attenuated by coembedding with fasudil (P < 0.01). Conclusions: These findings indicate that fasudil might have a therapeutic potential for ocular angiogenic diseases. The antiangiogenic effect of fasudil appears to be mediated through the blockade not only of Rho-kinase signaling but also of ERK and Akt signaling.

UR - http://www.scopus.com/inward/record.url?scp=41549109771&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41549109771&partnerID=8YFLogxK

U2 - 10.1007/s10384-007-0487-5

DO - 10.1007/s10384-007-0487-5

M3 - Article

C2 - 18369695

AN - SCOPUS:41549109771

VL - 52

SP - 16

EP - 23

JO - Japanese Journal of Ophthalmology

JF - Japanese Journal of Ophthalmology

SN - 0021-5155

IS - 1

ER -