Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy

Gael Cagnone, Sheetal Pundir, Charlotte Betus, Tapan Agnihotri, Anli Ren, Jin Sung -Kim, Noémie-Rose Harvey, Emilie Heckel, Mei Xi Chen, Anu Situ, Perrine Gaub, Nicholas Kim, Ashim Das, Severine Leclerc, Florian Wünnemann, Louis Berillon, Gregor Andelfinger, Sergio Crespo-Garcia, Alexandre Dubrac, Flavio A. Rezende, Clary B. Clish, Bruno Maranda, José Carlos Rivera, Lois E. H. Smith, Przemyslaw Sapieha and Jean-Sébastien Joyal ()
Additional contact information
Gael Cagnone: Université de Montréal
Sheetal Pundir: CHU Sainte-Justine Azrieli Research Center
Charlotte Betus: Université de Montréal
Tapan Agnihotri: CHU Sainte-Justine Azrieli Research Center
Anli Ren: CHU Sainte-Justine Azrieli Research Center
Jin Sung -Kim: CHU Sainte-Justine Azrieli Research Center
Noémie-Rose Harvey: Northern Ontario School Medicine
Emilie Heckel: Université de Montréal
Mei Xi Chen: CHU Sainte-Justine Azrieli Research Center
Anu Situ: CHU Sainte-Justine Azrieli Research Center
Perrine Gaub: CHU Sainte-Justine Azrieli Research Center
Nicholas Kim: CHU Sainte-Justine Azrieli Research Center
Ashim Das: Université de Montréal
Severine Leclerc: CHU Sainte-Justine Azrieli Research Center
Florian Wünnemann: CHU Sainte-Justine Azrieli Research Center
Louis Berillon: Université de Montréal
Gregor Andelfinger: CHU Sainte-Justine Azrieli Research Center
Sergio Crespo-Garcia: Université de Montréal
Alexandre Dubrac: Université de Montréal
Flavio A. Rezende: Université de Montréal
Clary B. Clish: The Broad Institute of MIT and Harvard University
Bruno Maranda: Université de Sherbrooke
José Carlos Rivera: CHU Sainte-Justine Azrieli Research Center
Lois E. H. Smith: Harvard Medical School
Przemyslaw Sapieha: Université de Montréal
Jean-Sébastien Joyal: Université de Montréal

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological neovessels to a physiological phenotype, hastening vascular regeneration of the ischemic retina and improving vision. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.

Date: 2025
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DOI: 10.1038/s41467-025-60061-4

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