Article
Lipid-derived angiogenic modulators: mechanistic investigations of ω3-PUFA effects in proliferative retinopathies
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Published: | September 21, 2010 |
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Background: VEGF-inhibitors have revolutionized the clinical treatment of angiogenic eye diseases. Similarly, lipid-derived angiogenic modulators have also been found to attenuate retinal neovascularization, but are mechanistically less well understood.
Methods: The effect of ω3-PUFAs on retinal angiogenesis was studied using the mouse model of oxygen-induced retinopathy (OIR). Mechanistic investigations were performed using various transgenic mouse strains and were validated with specific pharmacological inhibitors in vitro and in vivo.
Results: Supplementing ω3-PUFAs reduces retinal neovascularization by more than 40% in the OIR mouse model, similar to the effect seen with VEGF inhibition. The anti-angiogenic effect of ω3-PUFAs is abrogated in mice lacking the lipid metabolizing enzyme 5-lipoxygenase (5-Lox-/-). Among other functions, 5-Lox is essential for generating the anti-angiogenic lipid metabolite 4-HDHA, which binds to the nuclear receptor PPARγ and changes the gene expression profile of activated retinal endothelial cells to induce a less angiogenic state.
Conclusions: These results identify some critical steps in the mechanism of anti-angiogenic lipid signaling in the retina. Interestingly, the identified signaling cascade ω3-PUFA → 5-Lox enzyme → 4-HDHA metabolite → PPARγ receptor is independent of VEGF and may thus have additive effects clinically.