Physiological light upregulates Vascular endothelial Growth Factor and enhances choroidal Neovascularization via Peroxisome Proliferator-Activated receptor g coactivator-1 a in Mice

A ge-related macular degeneration (AMD) is a prominent cause of legal blindness worldwide. 1 Although it is difficult to measure light exposure in human subjects, several population-based studies have indicated the causality of intense light exposure, such as sunlight exposure, for the development of late AMD, 2–5 especially neovascular AMD that is choroidal neovascularization (CNV) in the elderly. Recent experimental studies have also suggested the association of light exposure and neovascular AMD, 6–9 although they have been based on a hypothesis that the reaction between the light and the increased amount of bisretinoids in retinal pigment epithelium (RPE) might be sufficient to induce VEGF upregulation or inflammation. A conventional animal model for light-induced toxicity on the retina has been a rodent model exposed to visible light with intensities with several thousand lux (lx), 10,11 that causes acute loss of photoreceptors. Recently, 3000 lx light was reported to induce CNV besides retinal degeneration 12 ; however, a considerable problem of the existing animal model of light toxicity is that the light intensities are unphysiologically strong, and it has been difficult to discuss the association of light exposure and AMD. For instance, mice entrain circadian rhythm with 0.1 lx light 13,14 and are maintained at 10 to 20 lx in experimental conditions; conversely, for humans, sunlight, that is around 50 000 lx, is just within physiological range, although it is often unpleasant. In the present study, we developed a mouse model of intense physiological light (IPL) exposure and studied its effects on RPE and CNV, pathogenic origins of neovascular AMD. All experiments in the present study were conducted according to ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and were approved by the Institutional Animal Research Committee of the University of Tokyo. Adult male mice 8 to 12 weeks old were used in all experiments, except Crx 2/2 mice which was used at the age of 8 weeks. rd1/rd1 mice were purchased from Saitama Experimental Animals Supply Co Ltd. Peroxisome proliferator-activated receptor  coactivator-1 (PGC-1) 2/2 mice were purchased form Jackson Laboratory. Estrogen-related receptor- (ERR-) 2/2 mice were kindly provided by Novartis Institutes for BioMedical Research Inc. All the mice used in this study were raised in a C57BL/6 background. Mice were kept under 5-to 10-lx (12 hours) light/dark (12 hours) cycle at 22°C, if not Objective—Toxicity of intense light to facilitate the development of neovascular age-related macular …

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