Research ArticleRetinal Disease

Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy

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Science Translational Medicine  26 Oct 2016:
Vol. 8, Issue 362, pp. 362ra144
DOI: 10.1126/scitranslmed.aaf9440

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Old but deadly

Diabetics often lose their sight, a result of poor blood supply to the retina. Oubaha and colleagues investigated how this oxygen deprivation leads to disease. They found that retinal cells do not simply die when oxygen-starved, rather they become senescent—a state in which the cells secrete a cocktail of undesirable molecules, in mice and humans. These cytokines drive more senescence, encourage abnormal blood vessel formation, and block healthy regeneration. Treatment of mice with a diabetes drug or a senescence inhibitor reduced retinal disease, suggesting that interrupting this process could be therapeutically beneficial.

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.

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