Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy

Abstract

Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.

NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence

“…Overexpression of either arginase isoform has been reported to promote senescence of HUVEC [15,16]. An association between diabetes and the development of SASP in retinal cells has also been reported [17,18]. However, the underlying mechanisms are not yet understood.…”

ER stress and unfolded protein response in ocular health and disease

“… found that retinal ischemia can trigger cellular senescence to protect retinal cells, which enables retinal cells to survive periods of limited metabolic supply and to escape hypoxia‐associated cell death in a mouse model of ischemic retinopathy. Interestingly, using transcriptome analysis combined with loss‐of‐functions genetics, Oubaha's results indicated that those cells require the activity of the endoribonuclease domain of IRE1α to promote senescence and adopt a senescence‐associated secretory Phenotype (SASP) . The presence of SASP‐associated cytokines, such as plasminogen activator inhibitor‐1 (PAI‐1), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), and VEGF were found to be present in the vitreous humor of patients suffering from proliferative DR.…”

“…Furthermore, they identified a clinical relevance of SASP inhibition using metformin, a widely used biguanide antidiabetic drug known to reduce SASP without interfering with the growth arrest program . They demonstrated that intravitreal injection of metformin into mice abolished SASP, decreased ER stress, and reduced retinal neovascularization and pathological retinal angiogenesis .…”

“…One of the central questions in ischemic retinopathies is how can retinal ganglion cells escape ischemia-induced cell death. A recent research study from Oubaha et al [89] have provided insight into why retinal neurons survive in ischemic retinopathies despite compromised metabolic supply and explored the function of cellular senescence. When a cell undergoes senescence, it acquires a permanent state of cell cycle arrest, in which cells remain viable [90].…”

“…When a cell undergoes senescence, it acquires a permanent state of cell cycle arrest, in which cells remain viable [90]. Oubaha et al [89] found that retinal ischemia can trigger cellular senescence to protect retinal cells, which enables retinal cells to survive periods of limited metabolic supply and to escape hypoxia-associated cell death in a mouse model of ischemic retinopathy. Interestingly, using transcriptome analysis combined with loss-of-functions genetics, Oubaha's results indicated Fig.…”