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Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition
Open accessAbstract
Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16 INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16 INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.
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“They identified a subset of senescent endothelial cells in the retina, which highly express Col1a1, that can be specifically eliminated by a senolytic drug [41].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [41]
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Metadata
- Authors
- Crespo-Garcia, S., Tsuruda, P. R., Dejda, A., Ryan, R. D., Fournier, F., Chaney, S. Y., Pilon, F., Dogan, T., Cagnone, G., Patel, P., Buscarlet, M., Dasgupta, S., Girouard, G., Rao, S. R., Wilson, A. M., O’Brien, R., Juneau, R., Guber, V., Dubrac, A., Beausejour, C., Armstrong, S., Mallette, F. A., Yohn, C. B., Joyal, J.-S., Marquess, D., Beltran, P. J., & Sapieha, P.
- Affiliations
- Unity Biotechnology (United States) (US)
- Hôpital Maisonneuve-Rosemont (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Corresponding author
- Tsuruda, Pamela R.
- Sapieha, Przemyslaw
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 33
- Issue
- 4
- Pages
- 818-832.e7
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3126392088
- Cited by
- 182
- References
- 81
- Citations by year
- 2026: 21 · 2025: 55 · 2024: 44 · 2023: 30 · 2022: 28 · 2021: 4
- FWCI
- 17.10
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- journal article
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- en
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- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Université de Montréal
- Canadian Diabetes Association (DI-3-18-5444-PS)
- Canadian Institutes of Health Research (148460)
- Fonds de Recherche du Québec - Santé
- Canada Research Chairs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- pathological angiogenesis, diabetic retinopathy, cellular senescence, BCL-XL inhibition, senolysis, p16INK4a, neovascularization, endothelial cells, COL1A1, anti-apoptotic therapy
- MeSH terms
- Collagen Type I, alpha 1 Chain, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Retinal Diseases, Tacrolimus, Cellular Senescence, Apoptosis, Cyclin-Dependent Kinase Inhibitor p16, Endothelial Cells, Flavonols, bcl-X Protein, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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