小柯机器人

加拿大蒙特利尔大学Przemyslaw Sapieha、Pamela R. Tsuruda等研究人员合作发现，视网膜病变中的病理性血管生成可通过BCL-xL抑制清除。该项研究成果于2021年2月5日在线发表在《细胞—代谢》杂志上。

研究人员证明，与健康的血管相反，病理性血管涉及到细胞衰老途径。糖尿病性视网膜病变患者的视网膜中以及在视网膜病变小鼠模型的破坏性新血管形成高峰期间，衰老（表达p16^INK4A）细胞发生积聚。通过使用清除p16^INK4A表达细胞的遗传方法或抗凋亡蛋白BCL-xL的小分子抑制剂，研究人员发现衰老细胞裂解（senolysis）可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不再检测到具有衰老特征并表达Col1a1的内皮细胞亚群，从而产生有利于生理性血管修复的视网膜。这些发现为支持BCL-xL抑制剂作为新生血管视网膜疾病的潜在疗法发展提供了机制证据。 

据了解，减轻以新血管形成为特征的疾病（如糖尿病性视网膜病）的病理性血管生成已改变了护理标准。关于区分生理性血管和病理性血管的分子标记知之甚少，这导致了治疗的脱靶效应。

附：英文原文

Title: Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition

Author: Sergio Crespo-Garcia, Pamela R. Tsuruda, Agnieszka Dejda, Rathi D. Ryan, Frederik Fournier, Shawnta Y. Chaney, Frederique Pilon, Taner Dogan, Gael Cagnone, Priyanka Patel, Manuel Buscarlet, Sonali Dasgupta, Gabrielle Girouard, Surabhi R. Rao, Ariel M. Wilson, Robert O’Brien, Rachel Juneau, Vera Guber, Alexandre Dubrac, Christian Beausejour, Scott Armstrong, Frederick A. Mallette, Christopher B. Yohn, Jean-Sebastien Joyal, Dan Marquess, Pedro J. Beltran, Przemyslaw Sapieha

Issue&Volume: 2021-02-05

Abstract: Attenuating pathological angiogenesis in diseases characterized by neovascularizationsuch as diabetic retinopathy has transformed standards of care. Yet little is knownabout the molecular signatures discriminating physiological blood vessels from theirdiseased counterparts, leading to off-target effects of therapy. We demonstrate thatin contrast to healthy blood vessels, pathological vessels engage pathways of cellularsenescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy andduring peak destructive neovascularization in a mouse model of retinopathy. Usingeither 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 analysisrevealed that subsets of endothelial cells with senescence signatures and expressingCol1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conduciveto physiological vascular repair. These findings provide mechanistic evidence supportingthe development of BCL-xL inhibitors as potential treatments for neovascular retinaldisease.

DOI: 10.1016/j.cmet.2021.01.011

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00011-5

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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