Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal QC H1T 2M4, Canada.
UNITY Biotechnology, 285 E Grand Avenue, South San Francisco, CA 94080, USA.
Cell Metab. 2021 Apr 6;33(4):818-832.e7. doi: 10.1016/j.cmet.2021.01.011. Epub 2021 Feb 5.
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.
在糖尿病性视网膜病变等新生血管疾病中，抑制病理性血管生成已经改变了治疗标准。然而，人们对于区分生理性血管和病理性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，与健康血管相比，病理性血管会激活细胞衰老途径。在糖尿病性视网膜病变患者的视网膜中，以及在视网膜病变的小鼠模型中破坏性新生血管生成的高峰期，都有衰老（p16 表达）细胞的积累。我们通过清除 p16 表达细胞的遗传方法或抗凋亡蛋白 BCL-xL 的小分子抑制剂，证明了衰老细胞的清除可以抑制病理性血管生成。单细胞分析显示，在 BCL-xL 抑制剂治疗的视网膜中，具有衰老特征并表达 Col1a1 的内皮细胞亚群不再被检测到，从而产生有利于生理性血管修复的视网膜。这些发现为 BCL-xL 抑制剂作为治疗新生血管性视网膜疾病的潜在治疗方法提供了机制证据。
