March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Lipid-derived Energy Shortage Precedes Subretinal Neovascularization In A Mouse Model Of Mactel
Author Affiliations & Notes
  • Jean-Sebastien Joyal
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Jing Chen
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Aimee Juan
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Colman J. Hatton
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Dorothy Pei
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Christian Hurst
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Molly R. Seaward
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Patrick Bherer
    Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
  • Bruno Maranda
    Genetics, Université de Sherbrooke, Sherbrooke, Quebec, Canada
  • Lois E. Smith
    Ophthalmology, Harvard University, Childrens Hospital, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  Jean-Sebastien Joyal, None; Jing Chen, None; Aimee Juan, None; Colman J. Hatton, None; Dorothy Pei, None; Christian Hurst, None; Molly R. Seaward, None; Patrick Bherer, None; Bruno Maranda, None; Lois E. Smith, None
  • Footnotes
    Support  MacTel Foundation (LEHS), Research to Prevent Blindness Senior Investigator Award (LEHS), Canadian Institute of Health Research Fellowship (JSJ), Charles H. Hood Foundation Research Award (JC)
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2991. doi:
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      Jean-Sebastien Joyal, Jing Chen, Aimee Juan, Colman J. Hatton, Dorothy Pei, Christian Hurst, Molly R. Seaward, Patrick Bherer, Bruno Maranda, Lois E. Smith; Lipid-derived Energy Shortage Precedes Subretinal Neovascularization In A Mouse Model Of Mactel. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2991.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Macular telangiectasia (MacTel) is a blinding disease of unknown etiology characterized by the development of pathological subretinal neovessels. Very low density lipoprotein receptor mutant mice (Vldlr-/-) exhibit the abnormal vascular phenotype of MacTel, resulting in photoreceptor degeneration. Vldlr is expressed in high energy consuming organs such as the retina and contributes to the uptake of fatty acids. Here we investigate the role of fatty acid β-oxidation during retinal development and how energy shortage may lead to pathological subretinal neovessels in Vldlr-/- mice.

Methods: : Subretinal vascular lesions of Vldlr-/- mice were characterized by confocal imaging of lectin-stained retinal flat mounts. Vldlr and Vegf expression was evaluated by immunofluoressence (IF) and qRT-PCR of laser-capture microdissected (LCM) retinal layers from Vldlr-/- and wild-type mice. Vascular corrosion cast were used to assess the integrity of choroidal vessels. Total acylcarnitine levels were measured by liquid chromatography followed by tandem mass spectrometry (LC/MS/MS).

Results: : Vldlr expression is localized (by LCM) to the outer nuclear layer (ONL) and the retinal-pigmented epithelium (RPE) of the outer retina, as well as to vessels. In Vldlr-/- mice, pathological neovessels originate from the deeper vascular plexus and breach the outer plexiform layer (OPL) between postnatal day (P) 12 and 14, when photoreceptor energy requirements surge. The first vascular lesions reach the retinal-pigmented epithelium (RPE) by P16. Choroidal vascular corrosion casts of Vldlr-/- were comparable to wild-type mice, suggesting a normal delivery of oxygen to the outer retina. Nonetheless, Vegf expression was increased in the ONL and RPE adjacent to subretinal neovessels (LCM). Because of the important role of VLDLR in lipid metabolism, we explored the energy derived through fatty acid β-oxidation in the retinas of our mice. Free carnitine and total acylcarnitine levels were significantly reduced in Vldlr-/- retinas (P12) compared to wild-type mice, suggesting a lipid-derived energy shortage preceding the appearance of vascular lesions.

Conclusions: : As the energy requirements of photoreceptors increase during development, an energy deficiency in lipid metabolism precedes the appearance of pathological neovessels in Vldlr-/- mice. This may be pertinent to the pathology of MacTel.

Keywords: retinal neovascularization • metabolism • photoreceptors 
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