June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Enhancing autophagy rescues pathological angiogenesis and improves vision in a model of retinal angiomatous proliferation
Author Affiliations & Notes
  • Charlotte Betus
    Department of Physiology and Pharmacology, Universite de Montreal, Montreal, Quebec, Canada
  • Emilie Heckel
    Department of Physiology and Pharmacology, Universite de Montreal, Montreal, Quebec, Canada
  • Gael Cagnone
    Department of Physiology and Pharmacology, Universite de Montreal, Montreal, Quebec, Canada
  • Tapan Agnihotri
    Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
  • Bertan Cakir
    Department of ophtalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Przemyslaw Mike Sapieha
    Department of ophtalmology, Universite de Montreal, Montreal, Quebec, Canada
  • Lois Smith
    Department of ophtalmology, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jean-Sebastien Joyal
    Department of Physiology and Pharmacology, Universite de Montreal, Montreal, Quebec, Canada
    Department of Pediatrics, Universite de Montreal, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Charlotte Betus None; Emilie Heckel None; Gael Cagnone None; Tapan Agnihotri None; Bertan Cakir None; Przemyslaw Mike Sapieha Unity Biotechnology, Code C (Consultant/Contractor); Lois Smith None; Jean-Sebastien Joyal None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3881. doi:
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      Charlotte Betus, Emilie Heckel, Gael Cagnone, Tapan Agnihotri, Bertan Cakir, Przemyslaw Mike Sapieha, Lois Smith, Jean-Sebastien Joyal; Enhancing autophagy rescues pathological angiogenesis and improves vision in a model of retinal angiomatous proliferation. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3881.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Retinal angiomatous proliferation (RAP) is a common subtype of neovascular age-related macular degeneration (NV-AMD) and a major cause of blindness. In NV-AMD, dysregulated glucose and lipid metabolism in photoreceptors might contribute to fuel shortages, which attracts pathological neovessels to restore energy homeostasis. Photoreceptors can undergo autophagy, a process by which they recycle intracellular nutrients to fuel mitochondria during starvation. Nutrient abundance generally suppresses autophagy, although the impact of lipids has been less explored. We show that excess circulating lipids restrain retinal autophagy contributing to pathological angiogenesis in a murine model of RAP.

Methods : Pathological RAP lesions were lectin-stained in Very low-density lipoprotein receptor-deficient (Vldlr-/-) retinas and a single-cell transcriptomics analysis was performed. Autophagy flux was measured by breeding CAG-RFP-EGFP-LC3 reporter mice with Vldlr-/- mice. Expression of TFEB, a master regulator of autophagy, was measured by western blot. The role of lipid excess on autophagy in Vldlr-/- was assessed by deleting Ffar1 (Ffar1-/-), a Free Fatty Acid Receptor sensitive to changes in circulating FFA. Rescue of NV-AMD using an autophagy agonist (HPβCD) was assessed by quantification of RAP-like vascular lesions at P16 and electroretinography at P30 in Vldlr-/-, Vldlr-/-Ffar1-/- and WT mouse.

Results : Since FA uptake is reduced in Vldlr-/- tissues, more remain in circulation, and the retina is fuel deficient, driving the formation of neovascular lesions reminiscent of RAP. Compared with control retinas, autophagy was one of the most dysregulated pathways in cone photoreceptors by single-cell transcriptomic analysis. Autophagy flux in reporter mice and TFEB expression were suppressed in Vldlr-/- retinas. TFEB levels were rescued by deleting Ffar1 in Vldlr-/- mice, which reduced the number of pathological RAP-like vascular lesions compared to Vldlr-/- retinas (57%; p<0.01). Increasing autophagy with HPβCD robustly decreased pathological RAP lesions and improved vision in Vldlr-/- mice.

Conclusions : Dysregulated autophagy by circulating lipids sensed by FFAR1 might contribute to photoreceptors’ energy failure driving neovascular eye diseases. Restoring autophagy may offer a novel therapeutic strategy to alleviate NV-AMD and improve vision.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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