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K. M. Connor, C. M. Aderman, J. Chen, A. Higuchi, J.-P. SanGiovanni, E. Y. Chew, D. Carper, N. N. Salem, L. E. H. Smith; Dietary -3 Long-Chain Polyunsaturated Fatty Acids Protect Against Pathological Retinal Neovascularization Through Modulation of Microglial Derived TNF-. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1965.
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Ocular neovascularization is the most common cause of blindness in all age groups. These sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. Included in these diseases are retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle aged adults. We studied the influence of ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFA) on vascular loss, vascular re-growth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy.
To induce vessel loss, postnatal day 7 (P7) mice with their nursing mothers were exposed to 75% oxygen for times ranging from 24 hours to 5 days. Vaso-obliteration was evaluated after 24 hours of oxygen exposure. Retinal neovascularization was evaluated 5 days after oxygen exposure (P7-P12) at P17 when the neovascular response is greatest. To study the effects of ω-3 LCPUFA on retinopathy mothers were fed (from P0) a diet enriched with ω-3 LCPUFA or a diet elevated in ω-6 LCPUFA. Additionally, the Fat-1 transgenic mouse was used to modify retinal ω-3 LCPUFA levels genetically. Retinal microglia were visualized from mice containing a CD11b driven GFP, and anti-TNF-α antibodies were utilized for TNF-α localization in retinal flatmounts.
We demonstrate that increasing ω-3 LCPUFA tissue levels by dietary and/or genetic means prevents pathological neovascularization by decreasing the vaso-obliterative phase thereby altering the hypoxic stimulus known to induce neovascularization. Animals fed the ω-6 LCPUFA diet had increases in TNF-α and severity of retinal neovascularization relative to those on an ω-3 LCPUFA rich diet. In TNF-α-/- mice the detrimental effect of the ω-6 diet is eliminated suggesting that the protective effects of ω-3 LCPUFA are mediated through TNF-α. Lastly, retinal microglia were found to be the primary source of TNF-α within the retina.
Our novel findings indicate that increasing sources of ω-3 LCPUFA decrease microglial TNF-α production and reduce pathologic angiogenesis. Our data suggest that these nutrients (often lacking in Western diets) significantly regulate pathological angiogenesis in the eye.
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