Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis (original) (raw)

Nature Medicine volume 13, pages 868–873 (2007)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Smith, L.E. et al. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 35, 101–111 (1994).
    CAS PubMed Google Scholar
  2. Crawford, M.A. et al. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies? Am. J. Clin. Nutr. 66, 1032S–1041S (1997).
    Article CAS Google Scholar
  3. Kermorvant-Duchemin, E. et al. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration. Nat. Med. 11, 1339–1345 (2005).
    Article CAS Google Scholar
  4. Fierro, I.M., Kutok, J.L. & Serhan, C.N. Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4). J. Pharmacol. Exp. Ther. 300, 385–392 (2002).
    Article CAS Google Scholar
  5. Fliesler, S.J. & Anderson, R.E. Chemistry and metabolism of lipids in the vertebrate retina. Prog. Lipid Res. 22, 79–131 (1983).
    Article CAS Google Scholar
  6. SanGiovanni, J.P. & Chew, E.Y. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog. Retin. Eye Res. 24, 87–138 (2005).
    Article CAS Google Scholar
  7. Calder, P.C. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot. Essent. Fatty Acids 75, 197–202 (2006).
    Article CAS Google Scholar
  8. Salem, N., Jr., Litman, B., Kim, H.Y. & Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36, 945–959 (2001).
    Article CAS Google Scholar
  9. Serhan, C.N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).
    Article CAS Google Scholar
  10. Kang, J.X., Wang, J., Wu, L. & Kang, Z.B. Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids. Nature 427, 504 (2004).
    Article CAS Google Scholar
  11. Moriguchi, T. et al. Effects of an n-3-deficient diet on brain, retina, and liver fatty acyl composition in artificially reared rats. J. Lipid Res. 45, 1437–1445 (2004).
    Article CAS Google Scholar
  12. Serhan, C.N., Arita, M., Hong, S. & Gotlinger, K. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers. Lipids 39, 1125–1132 (2004).
    Article CAS Google Scholar
  13. Hong, S., Gronert, K., Devchand, P.R., Moussignac, R.L. & Serhan, C.N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).
    Article CAS Google Scholar
  14. Tjonahen, E. et al. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem. Biol. 13, 1193–1202 (2006).
    Article CAS Google Scholar
  15. Arita, M. et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005).
    Article CAS Google Scholar
  16. Meder, W. et al. Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett. 555, 495–499 (2003).
    Article CAS Google Scholar
  17. Goukassian, D.A. et al. Tumor necrosis factor-α receptor p75 is required in ischemia-induced neovascularization. Circulation 115, 752–762 (2007).
    Article CAS Google Scholar
  18. Kishore, R. et al. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-α–induced transcriptional repression of cyclin A. J. Clin. Invest. 115, 1785–1796 (2005).
    Article CAS Google Scholar
  19. Gardiner, T.A. et al. Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am. J. Pathol. 166, 637–644 (2005).
    Article CAS Google Scholar
  20. Vassalli, P. The pathophysiology of tumor necrosis factors. Annu. Rev. Immunol. 10, 411–452 (1992).
    Article CAS Google Scholar
  21. Ritter, M.R. et al. Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J. Clin. Invest. 116, 3266–3276 (2006).
    Article CAS Google Scholar
  22. Checchin, D., Sennlaub, F., Levavasseur, E., Leduc, M. & Chemtob, S. Potential role of microglia in retinal blood vessel formation. Invest. Ophthalmol. Vis. Sci. 47, 3595–3602 (2006).
    Article Google Scholar
  23. Collart, M.A., Baeuerle, P. & Vassalli, P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB. Mol. Cell. Biol. 10, 1498–1506 (1990).
    Article CAS Google Scholar
  24. Millet, I. et al. Inhibition of NF-κB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide. J. Biol. Chem. 275, 15114–15121 (2000).
    Article CAS Google Scholar
  25. Duffield, J.S. et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J. Immunol. 177, 5902–5911 (2006).
    Article CAS Google Scholar
  26. Mukherjee, P.K., Marcheselli, V.L., Serhan, C.N. & Bazan, N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. USA 101, 8491–8496 (2004).
    Article CAS Google Scholar
  27. Arita, M. et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc. Natl. Acad. Sci. USA 102, 7671–7676 (2005).
    Article CAS Google Scholar
  28. Aiello, L.P. et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl. Acad. Sci. USA 92, 10457–10461 (1995).
    Article CAS Google Scholar
  29. Bannenberg, G.L. et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 174, 4345–4355 (2005).
    Article CAS Google Scholar
  30. Grounds, M.D. et al. Silencing TNFα activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice. Cell Tissue Res. 320, 509–515 (2005).
    Article CAS Google Scholar

Download references

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.

Author information

Author notes

  1. Kip M Connor and John Paul SanGiovanni: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA
    Kip M Connor, Chatarina Lofqvist, Christopher M Aderman, Jing Chen, Akiko Higuchi, Elke A Pravda & Lois E H Smith
  2. Division of Epidemiology and Clinical Research, National Eye Institute, 10 Center Drive, Bethesda, 20892, Maryland, USA
    John Paul SanGiovanni & Emily Y Chew
  3. Department of Pediatrics, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
    Chatarina Lofqvist
  4. Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, Massachusetts, USA
    Song Hong & Charles N Serhan
  5. Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Drive, Rockville, 20892, Maryland, USA
    Sharon Majchrzak & Norman Salem Jr
  6. Office of the Director, National Eye Institute, 31 Center Drive, Bethesda, 20892, Maryland, USA
    Deborah Carper
  7. Dept of Clinical Neurosciences, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
    Ann Hellstrom
  8. Department of Medicine, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, MA, USA
    Jing X Kang

Authors

  1. Kip M Connor
    You can also search for this author inPubMed Google Scholar
  2. John Paul SanGiovanni
    You can also search for this author inPubMed Google Scholar
  3. Chatarina Lofqvist
    You can also search for this author inPubMed Google Scholar
  4. Christopher M Aderman
    You can also search for this author inPubMed Google Scholar
  5. Jing Chen
    You can also search for this author inPubMed Google Scholar
  6. Akiko Higuchi
    You can also search for this author inPubMed Google Scholar
  7. Song Hong
    You can also search for this author inPubMed Google Scholar
  8. Elke A Pravda
    You can also search for this author inPubMed Google Scholar
  9. Sharon Majchrzak
    You can also search for this author inPubMed Google Scholar
  10. Deborah Carper
    You can also search for this author inPubMed Google Scholar
  11. Ann Hellstrom
    You can also search for this author inPubMed Google Scholar
  12. Jing X Kang
    You can also search for this author inPubMed Google Scholar
  13. Emily Y Chew
    You can also search for this author inPubMed Google Scholar
  14. Norman Salem Jr
    You can also search for this author inPubMed Google Scholar
  15. Charles N Serhan
    You can also search for this author inPubMed Google Scholar
  16. Lois E H Smith
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toLois E H Smith.

Ethics declarations

Competing interests

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

Rights and permissions

About this article

Cite this article

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

Download citation