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

• Published in: Cell metabolism Vol. 33; no. 4; pp. 818 - 832.e7
• Main Authors: Crespo-Garcia, Sergio, Tsuruda, Pamela R., Dejda, Agnieszka, Ryan, Rathi D., Fournier, Frederik, Chaney, Shawnta Y., Pilon, Frederique, Dogan, Taner, Cagnone, Gael, Patel, Priyanka, Buscarlet, Manuel, Dasgupta, Sonali, Girouard, Gabrielle, Rao, Surabhi R., Wilson, Ariel M., O’Brien, Robert, Juneau, Rachel, Guber, Vera, Dubrac, Alexandre, Beausejour, Christian, Armstrong, Scott, Mallette, Frederick A., Yohn, Christopher B., Joyal, Jean-Sebastien, Marquess, Dan, Beltran, Pedro J., Sapieha, Przemyslaw
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.04.2021
• Subjects: aging; angiogenesis; Animals; Apoptosis - drug effects; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - metabolism; BCL-xL; cellular senescence; Cellular Senescence - drug effects; Collagen Type I, alpha 1 Chain - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - deficiency; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; diabetes; Disease Models, Animal; Endothelial Cells - cytology; Endothelial Cells - metabolism; Female; Flavonols - chemistry; Flavonols - pharmacology; Flavonols - therapeutic use; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neovascularization, Pathologic; p16INK4A; retina; Retinal Diseases - drug therapy; Retinal Diseases - metabolism; Retinal Diseases - pathology; retinopathy; senolytic; Tacrolimus - analogs & derivatives; Tacrolimus - pharmacology; UBX1967; cellular senescence; UBX1967; retinopathy; BCL-xL; retina; angiogenesis; senolytic; aging; p16INK4A; diabetes; p16(INK4A)
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2021.01.011

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 (p16INK4A-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 p16INK4A-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. [Display omitted] •Senescent cells accumulate during diabetic retinopathy•Pathological vasculature engages p16INK4A and BCL-xL•Clearance of p16INK4A-expressing cells suppresses pathological angiogenesis•BCL-xL inhibitor UBX1967 eliminates senescent cells and suppresses neovascularization Pathological angiogenesis is a cardinal feature of retinopathies and cancer. Crespo-Garcia, Tsuruda, Dejda et al. demonstrate that diseased blood vessels can be discriminated by their propensity to engage pathways of cellular senescence. They show that targeting senescence effector/anti-apoptotic protein BCL-xL suppresses pathological angiogenesis, providing a target for elimination of deregulated neovascularization.