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Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis

Abstract

Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3- and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy1. We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy2. Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.

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Figure 1: Elevated levels of ω-3-PUFAs result in decreased vaso-obliteration and retinal neovascularization in mice.
Figure 2: ResolvinD1, resolvinE1 and neuroprotectinD1, derived from ω-3-PUFAs, protect against retinopathy with reductions in vaso-obliteration and neovascularization.
Figure 3: Dietary PUFA regulation of TNF-α in retinopathy.

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Acknowledgements

We thank C. DiMartino, N. Liu, J.-R. Mo and K. Percarpio for technical help and J.-Y. Tsai for discussions. We thank the US National Institutes of Health Office of Dietary Supplements. This research was generously supported by the V. Kann Rasmussen Foundation and the US National Institutes of Health (EY008670, EY017017, EY14811 (L.E.H.S.); 1F32 EY017789, 5 T32 EY07145 (K.M.C.); P50-DE016191, GM38765 (C.N.S.); and Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center, P01 HD18655). We thank the Juvenile Diabetes Research Foundation for fellowship support (J.C.). This work was also supported by the Research to Prevent Blindness Lew Wasserman Merit Award (L.E.H.S.). The sponsors had no role in the design or conduct of the study, in the collection, analysis and interpretation of data or in the preparation, review or approval of the manuscript.

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Correspondence to Lois E H Smith.

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C.N.S. is an inventor on patents held by Brigham and Women's Hospital that relate to novel composition of matter: isolation, characterization, and use in treating diseases. These patents are the subject of licensing agreements for Brigham and Women's Hospital and consultantships related to clinical development for C.N.S.

Supplementary information

Supplementary Fig. 1

Normal vascular regrowth. (PDF 16 kb)

Supplementary Fig. 2

Intraocular injections of the TNF-α receptor fusion protein in ω-6 fed mice. (PDF 85 kb)

Supplementary Fig. 3

DHA and EPA suppress TNF-α mRNA induction in LPS-activated macrophages. (PDF 54 kb)

Supplementary Table 1

Omega-6 and omega-3 PUFA diet analysis. (PDF 24 kb)

Supplementary Table 2

Fat-1 mouse diet analysis. (PDF 13 kb)

Supplementary Table 3

Resolvin and neuroprotectin detection in mice on an ω-6 or ω-3 PUFA diet. (PDF 16 kb)

Supplementary Table 4

Feed lot analysis. (PDF 19 kb)

Supplementary Methods (PDF 90 kb)

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Connor, K., SanGiovanni, J., Lofqvist, C. et al. Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 13, 868–873 (2007). https://doi.org/10.1038/nm1591

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