Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

J Exp Med. 2014 Feb 10;211(2):281-95. doi: 10.1084/jem.20131494. Epub 2014 Jan 20.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Astrocytes / metabolism
  • Ependymoglial Cells / metabolism*
  • Epoxide Hydrolases / deficiency
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Fatty Acids, Unsaturated / biosynthesis*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Receptors, Notch / metabolism*
  • Retinal Vessels / cytology
  • Retinal Vessels / growth & development*
  • Retinal Vessels / metabolism*
  • Signal Transduction
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • Fatty Acids, Unsaturated
  • Fbxw7 protein, mouse
  • Receptors, Notch
  • Ubiquitin-Protein Ligases
  • Epoxide Hydrolases
  • Amyloid Precursor Protein Secretases