Fasudil inhibits vascular endothelial growth factor–induced angiogenesis<i>in vitro</i>and<i>in vivo</i>

Yin, Lu; Morishige, Ken‐ichirou; Takahashi, Toshifumi; Hashimoto, Kae; Ogata, Seiji; Tsutsumi, Seiji; Takata, Keiko; Ohta, Tsuyoshi; Koyama, Jun; Takahashi, Kazuhiro; Kurachi, Hirohisa

doi:10.1158/1535-7163.mct-06-0689

Cited by 89 publications

(71 citation statements)

References 35 publications

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“…The GTPase RhoA mediates cell contraction by organizing actin filaments into stress fibres, and active RhoA is required for a variety of complex morphogenetic processes (11). RhoA activates ROCK, which plays an important role in the regulation of actin stress fibre organization (24).…”

Section: Discussionmentioning

confidence: 99%

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Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

Zhang

Ren

et al. 2012

Oncol Rep

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Abstract. The aim of this study was to investigate the effect of fasudil on lung carcinoma-conditioned endothelial cells (LCc-ECs). To obtain LCc-ECs, human umbilical vein endothelial cells (HUVECs) were treated with conditioned cell culture media from human A549 lung adenocarcinoma cells. The effect of fasudil on the viability of LCc-ECs was assessed using the MTT assay, in vitro invasive ability was evaluated using the transwell chamber assay and cytoskeletal changes were detected using fluorescein-labelled phalloidin immunocytochemistry. RhoA mRNA and p-MLC protein expression were measured using RT-PCR and western blotting. Fasudil significantly and dose-dependently inhibited LCc-EC proliferation and in vitro invasive ability. Fasudil also led to stress fibre breakage and fracture in LCc-ECs, indicating that fasudil impacts polymerisation of the cytoskeletal actin filament network. Expression of RhoA mRNA and protein expression of the ROCK substrate p-MLC were reduced by fasudil, suggesting that fasudil can inhibit RhoA/ROCK signalling and attenuate angiogenesis in LCc-ECs. This study indicates that fasudil is an anti-angiogenic agent with potential application for the treatment of cancer, especially lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

“…Yin et al (11) showed that fasudil inhibits VEGF-induced angiogenesis in vitro and in vivo. However, the effect of fasudil on lung carcinoma-conditioned endothelial cells (LCc-EC) has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

Zhang

Ren

et al. 2012

Oncol Rep

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“…Another study indicated that ROCK inhibitors promote VEGF-mediated proliferation and the neovascularization of endothelial cells in vitro (24). In the present study, we established a rat model of OIR as previously described (25)(26)(27)(28) to determine whether ROCK affects retinal neovascularization and to determine the effects of the ROCK inhibitor, FSD, on the expression of ICAM-1, HIF-1α, Bcl-2 and caspase-3. Using this model, we observed the NP region and retinal blood vessel networks around the optic nerve, examined the mRNA expression of ICAM-1, Bcl-2, caspase-3 and HIF-1α in samples from 3 treatment groups at different time points, and assessed the effects of FSD on the NP region and vascularization in the retina of rats with OIR.…”

Section: Introductionmentioning

confidence: 93%

“…Using this model, we observed the NP region and retinal blood vessel networks around the optic nerve, examined the mRNA expression of ICAM-1, Bcl-2, caspase-3 and HIF-1α in samples from 3 treatment groups at different time points, and assessed the effects of FSD on the NP region and vascularization in the retina of rats with OIR. We implemented a cyclic oxygen exposure protocol that was modified from previous studies on oxygen-induced retinopathy using rats (25)(26)(27). Hyperoxic experiments were conducted in an airtight glass container constructed in our laboratory.…”

Section: Introductionmentioning

confidence: 99%

Effects of a Rho kinase inhibitor on the sequential expression of ICAM-1, HIF-1α, Bcl-2 and caspase-3 in the retina of rats with oxygen-induced retinopathy

Wang

Chen

2013

International Journal of Molecular Medicine

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Abstract. The aim of the present study was to evaluate the effects of blocking the Rho kinase pathway on non-perfused regions and angiogenesis in the retina of rats using a rat model of oxygen-induced retinopathy (OIR) by observing the sequential expression of intercellular adhesion molecule-1 (ICAM-1), hypoxia-inducible factor-1 (HIF-1), B-cell lymphoma/leukemia-2 gene (Bcl-2) and caspase-3 mRNA following the administration of the Rho kinase inhibitor, fasudil (FSD). A total of 240 newborn rats were randomly divided into a normoxia control (N) group, a hyperoxia (H) group and a H + FSD (HF) group. The rats were sacrificed, and the eyes were enucleated from postnatal day (P)12 to P21. Samples were prepared for retinal flat mounts, mRNA and protein quantification. On P14, a higher number of circuitous retinal veins was observed in the H group compared with the HF group. In the HF group, the avascular area was significantly reduced compared with the H group on P18 (P<0.01). In the HF group, the mRNA expression of Bcl-2 was significantly increased on P15 compared with the N and H group (P<0.01). On P15 and P17 in the H group and on P13 in the HF group, the mRNA expression of ICAM-1 was significantly increased compared with the other groups (P<0.05). In the H and HF group, the expression of HIF-1α was significantly increased on P12 compared with the N group (P<0.05). On P19 and P21, HIF-1α expression was significantly increased to a maximum level in the HF group compared with the H and N group (P<0.01). In conclusion, these results suggest that FSD inhibits the expression of ICAM-1, assisting in the release of Bcl-2, suppressing caspase-3. In the HF group, the retinal flat mounts revealed that FSD had a vasorelaxant effect. On P18, a double-layered retinal vascular network was formed, and the number of non-perfused regions was significantly reduced. However, the late-phase peak expression of HIF-1α resulted in an inevitable increase in vascular endothelial growth factor expression and further accelerated neovascularization and vascular reconstruction in the immature retinal model.

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“…Using in vivo and in vitro angiogenic assays, several labs have reported that disruption of RhoA/ROCK signaling inhibits vascular endothelial growth factor (VEGF)-mediated endothelial cell activation [7,[14][15][16][17][18][19]. Moreover, tumor derived endothelial cells display an enhanced ability to organize into capillary networks, correlating with a constitutively high level of RhoA/ROCK signaling [20].…”

Section: Introductionmentioning

confidence: 99%

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

Montalvo¹,

Spencer²,

Hackathorn³

et al. 2012

CMM

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Abstract:The serine/threonine protein kinase paralogs ROCK1 & 2 have been implicated as essential modulators of angiogenesis; however their paralog-specific roles in endothelial function are unknown. shRNA knockdown of ROCK1 or 2 in endothelial cells resulted in a significant disruption of in vitro capillary network formation, cell polarization, and cell migration compared to cells harboring non-targeting control shRNA plasmids. Knockdowns led to alterations in cytoskeletal dynamics due to ROCK1 & 2-mediated reductions in actin isoform expression, and ROCK2-specific reduction in myosin phosphatase and cofilin phosphorylation. Knockdowns enhanced cell survival and led to ROCK1 & 2-mediated reduction in caspase 6 and 9 cleavage, and a ROCK2-specific reduction in caspase 3 cleavage. Microarray analysis of ROCK knockdown lines revealed overlapping and unique control of global transcription by the paralogs, and a reduction in the transcriptional regulation of just under 50% of VEGF responsive genes. Finally, paralog knockdown in xenograft angiosarcoma tumors resulted in a significant reduction in tumor formation. Our data reveals that ROCK1 & 2 exhibit overlapping and unique roles in normal and dysfunctional endothelial cells, that alterations in cytoskeletal dynamics are capable of overriding mitogen activated transcription, and that therapeutic targeting of ROCK signaling may have profound impacts for targeting angiogenesis.

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Fasudil inhibits vascular endothelial growth factor–induced angiogenesisin vitroandin vivo

Abstract: Vascular endothelial growth factor

Cited by 89 publications

References 35 publications

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

Fasudil inhibits lung carcinoma-conditioned endothelial cell viability and migration

Effects of a Rho kinase inhibitor on the sequential expression of ICAM-1, HIF-1α, Bcl-2 and caspase-3 in the retina of rats with oxygen-induced retinopathy

Rock1 & 2 Perform Overlapping and Unique Roles in Angiogenesis and Angiosarcoma Tumor Progression

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