Bioactive -3 LCPUFA Derivatives, Resolvins and Neuroprotectins, Inhibit Neovascularization in Oxygen Induced Retinopathy

Abstract

Purpose:: The resolvins (resolution phase interaction products) and neuroprotectins (including neuroprotectinD1, NPD1) are bioactive products derived from the ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Resolvins were first identified in resolving inflammatory exudates in tissues enriched with DHA. The contribution of resolvins and neuroprotectins in the regulation of angiogenesis has not yet been investigated. To determine if these bioactive products mediate the protective activities of ω-3 LCPUFAs against retinopathy, we assessed the role of resolvin family members, resolvinD1 (RvD1) and RvE1 and NPD1 in both vessel loss and pathological neovascularization in a mouse model of oxygen induced retinopathy.

Methods:: A physiological dose of NPD1, RvD1, RvE1 or saline (control) was administered intraperitoneally from postnatal day 6 (P6) to P17 or from P5 to P8 (10ng/day, comparable to levels found in the retinas of mice fed a physiologically elevated ω-3 LCPUFA diet). NPD1, RvD1, and RvE1 were not detected in the retinas of ω-6 LCPUFA fed mice. To induce vessel loss, mice were exposed to 75% O₂ from P7 to P12. Mice were sacrificed at P8 or P17. Retinas were stained with lectin and flatmounted for visualization with confocal microscopy. Vaso-obliteration (at P8 and P17) and neovascular tuft areas (at P17) for each bioactive compound were quantified and compared with the saline control.

Results:: RvD1-, RvE1- and NPD1-treated mice showed significantly reduced vaso-obliteration, (p≤0.0001) and neovascularization (p≤0.03) at P17 compared to saline controls. No differences in vessel loss were observed between RvD1, RvE1 or NPD1 treated mice and controls treated from P5 to P8, indicating that these ω-3 LCPUFA derivatives confer their protective actions against retinopathy via enhanced vessel re-growth, not protection from vessel loss.

Conclusions:: These findings suggest that the bioactive ω-3 LCPUFA derivatives RvD1, RvE1 and NPD1 are potent suppressors of retinal angiogenesis and serve their protective effect through modulation of vessel regrowth after vessel loss.

Keywords: neovascularization • lipids