Intense physiological light upregulates vascular endothelial growth factor and enhances choroidal neovascularization via peroxisome proliferator-activated receptor γ coactivator-1α in mice

Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1366-71. doi: 10.1161/ATVBAHA.112.248021. Epub 2012 Apr 19.

Abstract

Objective: Toxicity of intense light to facilitate the development of neovascular age-related macular degeneration has been a health concern although the mechanism remains unclear.

Methods and results: Effects of intense, but within physiological range, light on retinal pigment epithelium, a major pathogenic origin of age-related macular degeneration were studied in mice. Intense physiological light upregulated vascular endothelial growth factor (VEGF) expression in retinal pigment epithelium, independent of circadian rhythm, which resulted in enhancement of choroidal neovascularization. In rd1/rd1 mice or Crx(-/-) mice that do not possess outer segment structure, light exposure did not induce VEGF, indicating that VEGF upregulation by light depended on increased outer segment phagocytosis by retinal pigment epithelium. In retinal pigment epithelium cells phagocytosing increased amount of outer segment, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) not hypoxia-inducible factor-1α was induced, leading to VEGF upregulation. The VEGF upregulation and choroidal neovascularization enhancement were abrogated in PGC-1α(-/-) mice and estrogen-related receptor-α(-/-) mice, indicating the involvement of PGC-1α/estrogen-related receptor-α pathway.

Conclusions: Intense physiological light is involved in choroidal neovascularization through excess outer segment phagocytosis and VEGF upregulation mediated by PGC-1α in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Choroid / blood supply*
  • Choroidal Neovascularization / etiology*
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / metabolism
  • Genes, Reporter
  • Homeodomain Proteins / genetics
  • Humans
  • Light / adverse effects*
  • Macular Degeneration / etiology*
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phagocytosis / radiation effects
  • Photoperiod
  • RNA, Messenger / metabolism
  • Receptors, Estrogen / deficiency
  • Receptors, Estrogen / genetics
  • Retinal Photoreceptor Cell Outer Segment / metabolism
  • Retinal Photoreceptor Cell Outer Segment / radiation effects
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology
  • Retinal Pigment Epithelium / radiation effects*
  • Time Factors
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Transfection
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • ERRalpha estrogen-related receptor
  • Homeodomain Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Messenger
  • Receptors, Estrogen
  • Trans-Activators
  • Transcription Factors
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • cone rod homeobox protein
  • vascular endothelial growth factor A, mouse