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Müller Cells Regulate Notch Signaling And Retinal Angiogenesis Via The Soluble Epoxide Hydrolase‐Dependent Generation Of 19,20‐Dihydroxydocosapentaenoic Acid
Author(s) -
Fleming Ingrid,
Hu Jiong,
Popp Rüdiger,
Frömel Timo
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.568.25
Subject(s) - epoxide hydrolase 2 , notch signaling pathway , chemistry , angiogenesis , retinal , microbiology and biotechnology , hes1 , lipid signaling , biochemistry , signal transduction , biology , cancer research , enzyme
Soluble epoxide hydrolase (sEH) is a promising pharmacological target based on its enzymatic function of metabolizing potent bioactive substrates, epoxyeicosatrienoic acids (EETs), epoxydocosapentaenoic acids (EDPs) and other lipid epoxides to their corresponding diols. Despite many studies characterized the proangiogenic and anti‐inflammatory effect of EETs, the biological function of sEH in angiogenesis in vivo remains unclear. We found that the retinal angiogenesis was significant delayed in sEH ‐/‐ mice and was associated with reduced tip cell numbers and filopodia. This phenotype was associated with the induction of the Notch‐dependent transcription factors Hes1 and Hey1 and attenuated endothelial cell proliferation. sEH was mainly expressed in Müller glia cells and Müller glia cell specific sEH knockout mice displayed delayed retinal angiogenesis similar to sEH ‐/‐ mice. Lipid profile analyses revealed a significant decrease of the sEH metabolite 19,20‐dihydroxydocosapentaenoic acid (DHDP) in sEH ‐/‐ retinas compared to WT littermates. 19,20‐DHDP suppressed Notch signaling via inhibition of γ‐secretase in vitro, as well as rescued retinal vasculature defects in a Notch overactivating mutant (Fbxw7 iEC ) in vivo. Moreover, intravitreal injection of 19,20‐DHDP significant increased tip cell and filopodia number as well as primary vessel network density in sEH ‐/‐ mice retina. Our data demonstrated that Müller glia cells are involved in the development of the superficial retinal vasculature by secreting 19,20‐DHDP which inhibits γ‐secretase mediated Notch signaling.