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 retinopathy 1 . We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissionsCorrespondence should be addressed to L.E.H.S. (lois.smith@childrens.harvard.edu).. Supplementary information is available on the Nature Medicine website. COMPETING INTERESTS STATEMENTThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http:// www.nature.com/naturemedicine/. HHS Public AccessAuthor manuscript Nat Med. Author manuscript; available in PMC 2015 July 05. Published in final edited form as:Nat Med. 2007 July ; 13(7): 868-873. doi:10.1038/nm1591. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 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 pregnancy 2 . Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.Ocular neovascularization is the most common cause of blindness in all age groups: retinopathy of prematurity in children, diabetic retinopathy in working-age adults and agerelated macular degeneration in the elderly. In principle, destructive angiogenesis in the eye can be ameliorated by either direct inhibition of neovascularization or by controlling vessel loss in order to reduce the hypoxic stimulus that drives neovascularization. Retinopathy is modeled in the mouse eye with oxygen-induced vessel loss, which precipitates hypoxiainduced retinopathy, allowing for assessment of retinal vessel loss, vessel regrowth after injury and pathological angiogenesis 1 .The role of lipids in angiogenesis is just beginning to be defined 3,4 . The major polyunsaturated fatty acids (PUFA) found in the retina a...

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…Together, the present study and our previous report (28) demonstrate a central role of EDPs and EETs in angiogenesis and tumorigenesis, demonstrating that the CYP/sEH pathway plays a critical role in mediating the antiangiogenic and anticancer effects of omega-3 fatty acids (4,9). These findings also illustrate unique opportunities to treat pathological angiogenesis and cancers using omega-3 lipids.…”

“…These conflicting results can at least partially be explained by our findings of the opposite effects of EETs and EDPs on angiogenesis. Our findings further indicate that sEH could be a potential therapeutic target to treat retinal neovascularization, which is a major cause of blindness in humans (4). DHA is most enriched in retinal tissues, compromising ∼60% of polyunsaturated fatty acids in retina (18).…”

“…E pidemiological and preclinical evidence supports that a diet rich in omega-3 dietary fatty acids is correlated with reduced risks of angiogenic diseases such as macular degeneration (1)(2)(3)(4) and cancers (5)(6)(7)(8). However, the mechanisms by which omega-3 fatty acids inhibit angiogenesis and cancer are poorly understood.…”

Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice

“…17,18 RvD1, which possesses anti-inflammatory and pro-resolving ability in many process of inflammatory resolution, has demonstrated that it can attenuate inflammatory responses in ALI, 10,11 peritonitis, 19,20 kidney ischemia-reperfusion injury, 21 and retinopathy. 22 Here our study was focused on the effects of RvD1 on disruption of pulmonary barrier in ALI and was undertaken to investigate possible molecular and cellular mechanism of RvD1. Our results showed that the effect of 5 mg/kg RvD1 is potent, which is in accordance with the previous experiment.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…The beneficial effects of resolvin E1 were shown to originate from blocking stimulation of LTB 4 and inhibiting LTB 4 -induced NF-κB activation by binding to the LTB 4 receptor BLT1 [150]. A recent study has put forward supporting evidence that omega-3 fatty acids and their bioactive products significantly reduce pathological angiogenesis, both through reduction of hypoxic stimulus as well as through resolvin-mediated activity [151].…”