title: Excessive retinol intake exacerbates choroidal neovascularization through upregulated vascular endothelial growth factor in retinal pigment epithelium in mice.
abstract: As a part of the visual cycle, all-trans-retinol (all-trans-ROL), the major form of vitamin A in circulating blood, is transported to the retinal pigment epithelium (RPE). All-trans-ROL is essential for normal retina function. However, recent researches have shown that excessive retinol intake can cause increase of all-trans-retinal. This can lead to the accumulation of lipofuscin, which is important in the pathogenesis of retina degeneration disease, such as dry type age-related macular degeneration (AMD). Since there are few reports regarding the involvement of all-trans-ROL in exudative AMD, we investigated the effects of all-trans-ROL in vitro and in vivo. We evaluated vascular endothelial growth factor (VEGF) expression in ARPE-19 cells and THP-1 cells after all-trans-ROL treatment using ELISA and real-time RT-PCR. In-vitro tube formation assay was performed with HUVEC cells using the conditioned medium (CM) obtained from ARPE-19 cells treated with all-trans-ROL. Transcriptional activity of retinoic acid receptor (RAR) was evaluated using luciferase assay. In mice, VEGF expressions were investigated in the retina and RPE/choroid after three weeks of excessive oral retinol intake. Laser-induced choroidal neovascularization (CNV) models were evaluated after they were fed with various doses of retinol. VEGF mRNA expression and VEGF production were significantly increased in all-trans-ROL treated ARPE-19 cells, which were inhibited by an RAR antagonist LE540. In contrast, there were no significant changes in VEGF production in THP-1 cells. Transcriptional activity of RAR was upregulated by all-trans-ROL treatment in ARPE-19 cells. The CM, obtained from ARPE-19 cells treated with all-trans-ROL, induced more capillary-like tube formation than cells treated with control vehicles. In vivo, the high retinol diet group has increased VEGF expression in the RPE/choroid and larger lesion size was induced. Our results suggest that all-trans-ROL is a pro-angiogenic factor. Excessive retinoid intake may be a potential risk factor for exudative AMD.
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Xue
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Nishida
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Aoki
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Ophthalmology, University of Tokyo, School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: yanagi-tky@umin.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yanagi
mesh_terms: D000818:Animals; D002829:Choroid / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics*; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*; D014801:Vitamin A / Q000493:pharmacokinetics*; D014815:Vitamins / Q000493:pharmacokinetics
chemical_list: D042461:Vascular Endothelial Growth Factor A; D014815:Vitamins; D014801:Vitamin A; D012313:RNA
keywords: Angiogenesis; Moderator; VEGF; Visual cycle