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M. Miura, Y. Hata, T. Kita, S. Kawahara, R. Arita, S. Nakao, A. Hafezi-Moghadam, T. Ishibashi; Anti-Angiogenic Effects of Hmg-coa Reductase Inhibitor and Its Intracellular Signalings. Invest. Ophthalmol. Vis. Sci. 2008;49(13):530.
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While it has been reported that statins have inhibitory effects on angiogenesis, its precise mechanisms are still unclear. We addressed to clarify how statin exerts its anti-angiogenic effects by way of in vitro assays.
Bovine retinal microvascular endothelial cells (BRECs) and human umbilical vein endothelial cells (HUVECs) were used for in vitro assays. To estimate the effects of simvastatin, a HMG-CoA reductase inhibitor, on the proliferation, migration and tubeformation by endothelial cells, we performed cell proliferation assay, thymidine uptake test, boyden chamber assay and tube formation assay. To determine the mechanisms of anti-angiogenic efficacy of simvastatin, the effects of simvastatin on VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2), p44/42 MAP kinase and myosin light chain (MLC) and the expression of VEGFR2 or neuropilin-1 protein, co-receptor of VEGF165, were examined by western blot analyses.
VEGF-dependent proliferation, migration and tube formation by endothelial cells were potently interfered by the treatment with simvastatin in a dose-dependent manner. Simvastatin significantly suppressed VEGF-induced phosphorylation of VEGFR2, p44/42 MAP kinase and MLC without affecting the expression of VEGFR2 or neuropilin-1 protein.
These results indicated that the anti-angiogenic efficacy of statins appear to be caused by the suppression of VEGF-induced signalings via inhibition of VEGFR2 phosphorylation in endothelial cells at least in part.
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