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 (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.
Subject(s)
Cellular Senescence , Retinal Diseases/pathology , bcl-X Protein/metabolism , Animals , Apoptosis/drug effects , 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 , 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 , Retinal Diseases/drug therapy , Retinal Diseases/metabolism , Tacrolimus/analogs & derivatives , Tacrolimus/pharmacology , bcl-X Protein/antagonists & inhibitorsABSTRACT
Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.
