Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid.
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 Müller glia cells, and Müller cell-specific sEH deletion reproduced the sEH(-/-) retinal phenotype. Lipid profiling revealed that sEH deletion decreased retinal and Müller 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 γ-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 Müller cells.
Institute for Vascular Signaling, Centre for Molecular Medicine, Johann Wolfgang Goethe University and DZHK (German Centre for Cardiovascular Research) partner site Rhine-Main, 60590 Frankfurt, Germany.
Jiong
J
Hu
Rüdiger
R
Popp
Timo
T
Frömel
Manuel
M
Ehling
Khader
K
Awwad
Ralf H
RH
Adams
Hans-Peter
HP
Hammes
Ingrid
I
Fleming
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D063928:Ependymoglial Cells / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D051880:Receptors, Notch / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D005231:Fatty Acids, Unsaturated; C513272:Fbxw7 protein, mouse; D051880:Receptors, Notch; D044767:Ubiquitin-Protein Ligases; D004851:Epoxide Hydrolases; D053829:Amyloid Precursor Protein Secretases