Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy
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 fa...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60061-4 |
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| author | 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 Jean-Sébastien Joyal |
| author_facet | 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 Jean-Sébastien Joyal |
| author_sort | Gael Cagnone |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-636b4d38d7a64da2be60b816d4a01a49 |
| institution | Matheson Library |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-636b4d38d7a64da2be60b816d4a01a492025-06-29T11:13:23ZengNature PortfolioNature Communications2041-17232025-06-0116111510.1038/s41467-025-60061-4Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathyGael Cagnone0Sheetal Pundir1Charlotte Betus2Tapan Agnihotri3Anli Ren4Jin Sung -Kim5Noémie-Rose Harvey6Emilie Heckel7Mei Xi Chen8Anu Situ9Perrine Gaub10Nicholas Kim11Ashim Das12Severine Leclerc13Florian Wünnemann14Louis Berillon15Gregor Andelfinger16Sergio Crespo-Garcia17Alexandre Dubrac18Flavio A. Rezende19Clary B. Clish20Bruno Maranda21José Carlos Rivera22Lois E. H. Smith23Przemyslaw Sapieha24Jean-Sébastien Joyal25Department of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Azrieli Research CenterDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterDepartment of General Surgery, Northern Ontario School MedicineDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Azrieli Research CenterCHU Sainte-Justine Azrieli Research CenterDepartment of Pharmacology and Physiology, Université de MontréalCHU Sainte-Justine Azrieli Research CenterOptometry School, Université de MontréalDepartment of Pharmacology and Physiology, Université de MontréalDepartment of Ophthalmology, Université de MontréalMetabolomics Platform, The Broad Institute of MIT and Harvard UniversityDepartment of Pediatrics, Université de SherbrookeCHU Sainte-Justine Azrieli Research CenterDepartment of Ophthalmology, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Ophthalmology, Université de MontréalDepartment of Pharmacology and Physiology, Université de MontréalAbstract 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.https://doi.org/10.1038/s41467-025-60061-4 |
| spellingShingle | 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 Jean-Sébastien Joyal Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy Nature Communications |
| title | Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| title_full | Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| title_fullStr | Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| title_full_unstemmed | Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| title_short | Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| title_sort | metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy |
| url | https://doi.org/10.1038/s41467-025-60061-4 |
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