Cone Photoreceptors Can Generate the Potent Neurotrophic and Pro-angiogenic Fatty Acid Amide Erucamide

Abstract

Purpose: Highly energy-demanding photoreceptors require a stable vasculature to function properly. Attenuation of the vasculature is observed in many cases of age-related macular degeneration (AMD) and retinitis pigmentosa (RP). We showed previously that stabilizing the vasculature slows photoreceptor degeneration in mice. We report here that cone photoreceptors synthesize vasculotrophic bioreactive lipids.

Methods: Untargeted mass spectrometry-based metabolomic assays were performed on dystrophic and normal eyes. Candidate factors were injected intravitreally and the effects were examined using OCT, histology, and angiography. Candidate genes were overexpressed using in vivo electroporation or viral transduction. Gene profiling experiments were performed to elucidate molecular pathways. Cytokine levels were examined from human vitreous samples.

Results: The fatty acid amide erucamide (22:1) is one of the most abundant metabolites in wild-type eyes and one of the most dysregulated during degeneration. It is potently pro-angiogenic; subretinal injections induce pronounced choroidal and intraretinal neovascularization three days post injection. Low doses significantly slow photoreceptor degeneration in mice. Peptidylglycine alpha-amidating monoxygenase (PAM), a protein expressed in cone outer segments of fish, mice, and humans, likely controls its biosynthesis. Genetic gain and loss-of-function of PAM induces neovascularization and vessel attenuation respectively. Gene-profiling experiments and histology revealed that the pro-angiogenic gene angiogenin is upregulated by erucamide in Muller glia. Forced overexpression of angiogenin in Muller glia also results in neovascularization. Finally, angiogenin is upregulated in vitreous samples of patients with various diseases including AMD and RP.

Conclusions: Cone photoreceptor-derived erucamide exerts critical vasculo- and neurotrophic functions. Some of the effects of erucamide may be mediated by Muller glia-derived angiogenin, and the detection of angiogenin in human diseased samples suggests it may be pathological. Elucidating the normal and pathological functions of the erucamide/angiogenin pathway may be useful for the development of novel neurotrophic agents.

Keywords: 615 neuroprotection • 700 retinal neovascularization • 592 metabolism