Cited by 184Telomeres, Telomerase, and SenescenceRetinal Diseases and TreatmentsAngiogenesis and VEGF in Cancer

Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

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Crespo-Garcia, Sergio, Tsuruda, Pamela R., Dejda, Agnieszka, Ryan, Rathi D., Fournier, Frederik, Chaney, Shawnta Y., Pilon, Frederique, Dogan, Taner +19 more·2021·Cell Metabolism

Abstract

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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Crossref · 10.1016/j.cmet.2021.01.011

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  • A subset of senescent endothelial cells in the retina highly express Col1a1 and can be specifically eliminated by a senolytic drug.

    “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].”

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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
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
Type
journal article
Language
en
Open access
Locations
  • 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
  • Health Sciences › Medicine › Physiology › 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

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