Bioactive epoxy-fatty acid levels are determined by the activity of the cytochrome P450 enzyme that generates them and the soluble epoxide hydrolase (sEH) which metabolizes them to diols. To investigate the role of epoxides and diols in angiogenesis we studied responses in sEH^-/- mice.

Retinal vascularisation was markedly delayed in sEH^-/- mice 2 and 5 days after birth, and was associated with reduced tip cell numbers and filipodia extensions, the induction of the Notch-dependent transcription factors Hes1 and Hey1 and attenuated endothelial cell proliferation. The 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 demonstrate 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.