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Endoplasmic Reticulum Stress Delays Choroid Development in the HCAR1 Knockout Mouse
Monir Modaresinejad1, Xiaojuan Yang2, Mohammad A Mohammad Nezhady3
1Program in Biomedical Science, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada; Department of Pediatrics, Ophthalmology and Pharmacology, Centre de Recherche du CHU Sainte-Justine, Montréal, Quebec, Canada.
Lactate signaling through hydroxycarboxylic acid receptor 1 (HCAR1) is crucial for choroidal blood vessel development. HCAR1 deficiency impairs choroidal vasculature, impacting vision, but can be rescued by inhibiting stress responses.
Area of Science:
- Ophthalmology
- Vascular Biology
- Cellular Metabolism
Background:
- The subretina, including the choroid and retinal pigment epithelium (RPE), is vital for vision.
- RPE cells utilize lactate from glycolysis for energy and signaling.
- Hydroxycarboxylic acid receptor 1 (HCAR1) mediates lactate's biological effects.
Purpose of the Study:
- To investigate the role of HCAR1 in subretinal development and function.
- To determine the impact of HCAR1 deficiency on choroidal vasculature and RPE cells.
Main Methods:
- Utilized Hcar1 knockout (Hcar1-/-) mice.
- Analyzed choroidal vasculature development and RPE cell characteristics.
- Assessed endoplasmic reticulum stress and protein translation rates.
Main Results:
- HCAR1 is exclusively expressed in RPE cells.
- Hcar1-/- mice showed thinner choroidal vasculature and impaired angiogenesis.
- HCAR1 deficiency led to increased ER stress, eIF2α phosphorylation, and reduced protein translation and proliferation.
- Inhibiting the integrated stress response rescued choroidal thinning.
Conclusions:
- Lactate signaling via HCAR1 is essential for choroidal development and angiogenesis.
- HCAR1 plays a critical role in maintaining RPE function and overall vision.
- Targeting the integrated stress response may offer therapeutic potential for vision disorders.
