New therapeutic target for optimizing retina ischemic tissue revascularization

Theme: Retina*
What: Retina
Part of: Retina II: Stamping out Blindness and Restoring Sight / Rétine II: Lutter contre la cécité et redonner la vue
When: 6/1/2024, 04:15 PM - 05:45 PM
Where: Room | Salle 713 AB

Abstract

Purpose: To define distinct metabolic and transcriptional signatures for physiological and pathological vessels in retina.

Study design: Basic (experimental)

Methods: We used a multiomics approach to study the metabolic hallmarks of physiological and pathological angiogenesis in proliferative retinopathies and to identify transcriptional signature for pathological neovessels.

Results: Physiological angiogenesis revascularizes the ischemic retina, while misguided pathological neovessels grow towards the vitreous. We analysed the metabolite profile in vitreous humor samples from patients with proliferative diabetic retinopathy. We observed an accumulation of fatty acyl carnitines, by-products of mitochondrial fatty-acid-oxidation (FAO) in diabetic retinopathy samples compared to controls. In mouse PR, using unbiased large-scale approaches combining metabolomics and single-cell transcriptomics, we observed distinct metabolic pathways define glycolytic migratory tip endothelial cells (ECs), essential to the regenerative process, and misguided yet actively proliferating neovascular endothelial cells (nvECs) that rely instead on fatty acid oxidation. Direct comparison showed 449 differentially expressed genes (DEGs) between healthy tip EC and nvEC (P value < 0.05, log2(FC) > 0.5. nvECs up-regulated genes were significantly enriched in FAO pathways whereas tip ECs were enriched for glycolysis pathways. Inhibition of FAO in ischemic retina shifted the metabolism to glycolysis, accelerated physiological revascularization and, improved visual function as measured by electroretinography (ERG) in murine model.

Conclusions:Providing metabolic supply to ischemic neurons preserves function. In proliferative retinopathies, a prevalent cause of blindness globally, misdirected pathological neovascular tufts often emerge in lieu of needed physiological revascularization of the ischemic neuroretina. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy. Fatty acid oxidation (FAO) metabolites accumulated in human and murine PR samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and mitigated tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological ECs to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. Our findings have implications for other neuro-ischemic conditions like stroke, where enhancing regenerative angiogenesis could preserve neuronal function.

Presenter(s)

Presenting Author: Sheetal Pundir

Additional Author(s):

Gael Cagnone, CHU St Justine Hospital, University de Montreal

Jean S. Joyal, CHU St-Justine, Univerity de Montreal

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