Purchase this article with an account.
Peter D Westenskow, Yoshihiko Usui, Toshihide Kurihara, Edith Aguilar, Daniel Feitelberg, Carli M Wittgrove, Ashley Barnett, Salome Murinello, Stephen Bravo, Martin Friedlander; . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):60.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Photoreceptors are some of the most metabolically demanding cells in the human body. The extraretinal choriocapillaris is the primary blood supply for photoreceptors, and attenuation of the choriocapillaris results in retinal degeneration. Photoreceptors are separated from the choriocapillaris by the RPE, and RPE cells are thought to be solely responsible for maintenance of the extraretinal vasculature. We showed previously that the bioreactive fatty acid amide erucamide may be produced by photoreceptors, and that it exerts profound pro-angiogenic effects on endothelial cells in the extra- and intraretinal vasculature. We also showed that erucamide may be synthesized by the multifunctional enzyme peptidylglycine alpha-amidating monoxygenase (PAM), which is expressed in photoreceptor outer segments in multiple species (suggesting that its function is evolutionary conserved.)
To examine the function of PAM in the retina, we generated transgenic mice using “conditional ready” gene-trap technology. A LacZ cassette with flanking frt sites was inserted in intron 1 of Pam to disrupt normal gene-splicing and to induce nonsense- mediated decay of Pam mRNA. Germ-line deletion of the cassette with flippase mice generates “wild-type” alleles (LoxP sites flank critical exon 2). Pam was conditionally deleted in photoreceptors using Crx-Cre. The effects were examined using immunohistochemistry, electron microscopy, angiography, and electroretinography.
In multiple rodent models of retinal degeneration PAM is dysregulated in a manner consistent with erucamide dysregulation and photoreceptor atrophy. Conditional ablation of PAM in murine photoreceptors induces profound attenuation of the choroidal and intraretinal vasculature, while gain-of-function assays induce massive and rapid neovascularization. Conditional deletion of Pam also results in profound cone dysfunction in electroretingrams, confirming its importance for retinal homeostasis.
Based on these observations, we propose a novel function for photoreceptors: biosynthesis of a small molecule metabolite with potent pro-angiogenic potential. Synthesis of erucamide by PAM is imperative for neuronal/vascular cross-talk and for vascular maintenance of the extra- and intraretinal vasculature.
This PDF is available to Subscribers Only