Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 211, Issue 2, Pages 281-295Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20131494
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Funding
- Deutsche Forschungsgemeinschaft [SFB-TR 23/A6, GRK 880, Exzellenzcluster 147 Cardio-Pulmonary Systems]
- China Scholarship Council (CSC)
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Cytochrome P450 (CYP) epoxygenases generate bioactive lipid epoxides which can be further metabolized to supposedly less active diols by the soluble epoxide hydrolase (sEH). As the role of epoxides and diols in angiogenesis is unclear, we compared retinal vasculature development in wild-type and sEH(-/-) mice. Deletion of the sEH significantly delayed angiogenesis, tip cell, and filopodia formation, a phenomenon associated with activation of the Notch signaling pathway. In the retina, sEH was localized in Muller glia cells, and Muller cell-specific sEH deletion reproduced the sEH(-/-) retinal phenotype. Lipid profiling revealed that sEH deletion decreased retinal and Muller cell levels of 19,20-dihydroxydocosapentaenoic acid (DHDP), a diol of docosahexenoic acid (DHA). 19,20-DHDP suppressed endothelial Notch signaling in vitro via inhibition of the gamma-secretase and the redistribution of presenilin 1 from lipid rafts. Moreover, 19,20-DHDP, but not the parent epoxide, was able to rescue the defective angiogenesis in sEH(-/-) mice as well as in animals lacking the Fbxw7 ubiquitin ligase, which demonstrate strong basal activity of the Notch signaling cascade. These studies demonstrate that retinal angiogenesis is regulated by a novel form of neuroretina-vascular interaction involving the sEH-dependent generation of a diol of DHA in Muller cells.
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