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

Author

Listed:
  • Gael Cagnone

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center)

  • Sheetal Pundir

    (CHU Sainte-Justine Azrieli Research Center
    McGill University)

  • Charlotte Betus

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center)

  • Tapan Agnihotri

    (CHU Sainte-Justine Azrieli Research Center
    McGill University)

  • Anli Ren

    (CHU Sainte-Justine Azrieli Research Center
    Zhongnan Hospital of Wuhan University)

  • Jin Sung -Kim

    (CHU Sainte-Justine Azrieli Research Center
    McGill University)

  • Noémie-Rose Harvey

    (Northern Ontario School Medicine)

  • Emilie Heckel

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center)

  • 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
    McGill University)

  • Ashim Das

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center)

  • Severine Leclerc

    (CHU Sainte-Justine Azrieli Research Center)

  • Florian Wünnemann

    (CHU Sainte-Justine Azrieli Research Center
    Bioquant)

  • Louis Berillon

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center)

  • Gregor Andelfinger

    (CHU Sainte-Justine Azrieli Research Center
    Université de Montréal)

  • Sergio Crespo-Garcia

    (Université de Montréal)

  • Alexandre Dubrac

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center
    Université de Montréal
    Université de Montréal)

  • Flavio A. Rezende

    (Université de Montréal
    Hôpital Maisonneuve-Rosemont)

  • 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
    Université de Montréal)

  • Lois E. H. Smith

    (Harvard Medical School)

  • Przemyslaw Sapieha

    (Université de Montréal
    Hôpital Maisonneuve-Rosemont)

  • Jean-Sébastien Joyal

    (Université de Montréal
    CHU Sainte-Justine Azrieli Research Center
    McGill University
    Université de Montréal)

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.

Suggested Citation

  • 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 & S, 2025. "Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60061-4
    DOI: 10.1038/s41467-025-60061-4
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