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Takashi Ueta, Tatusya Inoue, Kentaro Yuda, Takahisa Furukawa, Yasuo Yanagi, Yasuhiro Tamaki; Intense Physiological Light Upregulates VEGF and Promotes Choroidal Neovascularization via PGC-1α/ERR-α Pathway. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6482.
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Toxicity of intense light to facilitate the development of age-related macular degeneration (AMD), especially neovascular AMD, is a major public health concern although the mechanism remains unclear. We report the effects of intense, but within physiological range, light on retinal pigment epithelium (RPE), a major pathogenic origin of AMD.
In this study intense physiological light was defined as 15 lx visible light because wild-type (WT) mice escaped from visible light with intensity of >10 lx. Rhodopsin concentration in RPE was measured to compare the volume of phagocytosed photoreceptor outer segments (OS) among different intensities of light. rd1/rd1 mice and Crx–/– mice were used to evaluate the effect of light in mice without OS. mRNA and protein level of vascular endothelial growth factor-A (VEGF-A), Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and hypoxia-inducible factor 1 (HIF-1α) were evaluated by real-time RT-PCR and western blotting. ARPE-19 cells and isolated porcine OS were used to investigate the mechanism of OS-induced VEGF-A upregulation in RPE cells. PGC-1α–/– mice and estrogen-related receptor-α (ERR-α)–/– mice were used to confirm the involvement of PGC-1α/ ERR-α pathway in the light-induced VEGF-A upregulation in RPE. The mouse model of laser-induced choroidal neovascularization (CNV) was used to evaluate the effect of light.
Intense physiological light upregulated VEGF-A mRNA and protein level in RPE, independent of circadian rhythm, which led to the promotion of CNV in mice. In this process the increased phagocytosis of OS by RPE cells was observed in mice under intense physiological light, but not in mice under milder light. In rd1/rd1 mice and Crx–/– mice VEGF-A was not upregulated by light. In RPE cells phagocytosing more OS, increased expression of PGC-1α, not HIF-1α was observed. The VEGF-A upregulation and CNV promotion were abrogated in PGC-1α–/– mice and ERR-α–/– mice.
These results indicate that intense physiological light upregulates VEGF in RPE and promotes CNV, which is mediated by increased phagocytosis of OS by RPE and activation of PGC-1α/ ERR-α pathway. A direct evidence for the association of light exposure and CNV facilitation is provided by this report.
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