Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition
Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition
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DOI：
10.1016/j.cmet.2021.01.011
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发表时间：
2021-04-06
期刊：
影响因子：
29
通讯作者：
Sapieha, Przemyslaw
中科院分区：
文献类型：
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作者：
Crespo-Garcia, Sergio;Tsuruda, Pamela R.;Sapieha, Przemyslaw
在以新血管形成为特征的疾病（如糖尿病视网膜病变）中减弱病理性血管生成已经改变了护理标准。然而，人们对区分生理血管和病变血管的分子特征知之甚少，这导致了治疗的脱靶效应。我们证明，与健康血管相反，病理血管参与细胞衰老的途径。衰老（p16（INK 4A）-表达）细胞在糖尿病视网膜病变患者视网膜和视网膜病变小鼠模型中峰值破坏性新血管形成期间积累。无论是使用遗传方法，清除p16（INK 4A）表达细胞或小分子抑制剂的抗凋亡蛋白BCL-xL，我们表明，senolysis抑制病理性血管生成。单细胞分析显示，在BCL-xL抑制剂处理的视网膜中不再检测到具有衰老特征并表达Col 1a 1的内皮细胞亚群，从而产生有利于生理血管修复的视网膜。这些发现提供了支持开发BCL-xL抑制剂作为新生血管性视网膜疾病的潜在治疗的机制证据。
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(INK4A)-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(INK4A)-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.