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-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-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.
About The Expert
Sergio Crespo-Garcia
Pamela R Tsuruda
Agnieszka Dejda
Rathi D Ryan
Frederik Fournier
Shawnta Y Chaney
Frederique Pilon
Taner Dogan
Gael Cagnone
Priyanka Patel
Manuel Buscarlet
Sonali Dasgupta
Gabrielle Girouard
Surabhi R Rao
Ariel M Wilson
Robert O’Brien
Rachel Juneau
Vera Guber
Alexandre Dubrac
Christian Beausejour
Scott Armstrong
Frederick A Mallette
Christopher B Yohn
Jean-Sebastien Joyal
Dan Marquess
Pedro J Beltran
Przemyslaw Sapieha
References
PubMed