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Joseph L Wilkerson, Hui Qi, Hunter Porter, Megan Stiles, Nawajes A Mandal; Sphingolipid signaling in corneal neovascularization. . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4494.
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© ARVO (1962-2015); The Authors (2016-present)
Sphingosine-1-phosphate (S1P) is a widely studied sphingolipid signaling mediator that acts as a ligand for five cell surface receptors, S1P1-5. Activation of these g-protein-coupled receptors is linked to cell proliferation, differentiation, inflammatory responses, angiogenesis, and neovascularization (NV). Sphingosine kinases (SphK) are responsible for the phosphorylation of sphingosine to S1P, yet their role in ocular vascularization is currently unknown. The purpose of this study is to assess role of S1P in ocular neovascularization through the role of SphK. Docosahexaenoic acid (DHA), an ω-3 fatty acid is also known for its role in protecting from retinal NV. We have also tested an interesting hypothesis that S1P mediates the protective action of DHA for reducing NV.
SPHK1 knockout mice were bred with mice containing the transgene, Fat1. FAT1 is able to convert ω-6 polyunsaturated fatty acids (PUFA) to ω-3 PUFA; mice containing the transgene therefore have elevated amounts of DHA when placed on a diet of 10% safflower oil containing only ω-6 PUFA. Litters of mice starting with the second generation of breeders on the diet were used for corneal alkali burns as a NV model. After a 10 day period following the initial alkali burn the corneas were harvested and used for immunohistochemistry to determine NV.
Ten days after the alkali burn wild type cornea exhibit a large amount of NV originating in a completely disrupted limbus toward the central cornea. Sphk1 knockout mice have dramatically reduced neovascularization extending from the limbus. In respect to DHA, wild type mice that contain Fat1 show protection from NV, while mice that lack SphK1 and contain Fat1 show similar patterns of NV as Sphk1 knockout mice alone.
We conclude that SphK1 plays a major role in neovascular development in the cornea. We also found that DHA can protect the cornea from NV. Furthermore, this protective mechanism is mediated by SphK1, most likely through the generation of S1P.
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