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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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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.
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).
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.
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.
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