YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis
YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis
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YAP 通过改变 PFKFB3 驱动的内皮糖酵解促进眼部新生血管形成
DOI：
10.1007/s10456-020-09760-8
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发表时间：
2021-01-05
期刊：
影响因子：
9.8
通讯作者：
Yuan, Fei
中科院分区：
文献类型：
--
作者：
Feng, Yifan;Zou, Rong;Yuan, Fei
眼部新生血管是多种眼部疾病中视力损害的主要原因，例如年龄相关性黄斑变性和早产儿视网膜病变。近年来的研究表明，Hippo信号通路下游的yes相关蛋白（雅普）参与了病理性血管生成，但其具体机制尚不清楚。在这里，我们证明，缺氧处理触发雅普的表达和核转位的人脐静脉内皮细胞（HUVEC）。雅普作为转录共激活因子与转录增强子激活域1（TEAD 1）一起作用，结合关键糖酵解调节因子6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）的启动子，从而增加PFKFB 3的表达。此外，沉默雅普抑制缺氧条件下HUVECs的糖酵解以及增殖、迁移、出芽和管形成，所有这些都可以被PFKFB 3的增强表达所逆转。最后，我们的动物研究还表明，玻璃体内注射小干扰RNA的雅普或PFKFB 3显着抑制脉络膜新生血管和氧诱导视网膜病变的小鼠模型中的新生血管生长。这些发现为以前未认识到的雅普对内皮糖酵解的作用提供了新的见解，并突出了靶向雅普/PFKFB 3轴在治疗眼部新生血管中的潜力。
Ocular neovascularization is the leading cause of vision impairment in a variety of ocular diseases, such as age-related macular degeneration and retinopathy of prematurity. Emerging studies have suggested that the yes-associated protein (YAP), a downstream effector of the Hippo pathway, is involved in the pathological angiogenesis, but the mechanism are largely unknown. Here, we demonstrated that hypoxic treatment triggered YAP expression and nuclear translocation in human umbilical vein endothelial cells (HUVECs). YAP acted as a transcriptional co-activator working together with transcriptional enhancer activator domain 1 (TEAD1) to binds the promoter of the key glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3), and thereby increases PFKFB3 expression. Moreover, silencing of YAP inhibited glycolysis as well as proliferation, migration, sprouting and tube formation of HUVECs under hypoxia, all of which could be reversed by enforced expression of PFKFB3. Finally, our animal study also showed that intravitreal injection of small interfering RNA of YAP or PFKFB3 dramatically suppressed the neovascular growth in mouse models of choroidal neovascularization and oxygen-induced retinopathy. These findings provide new insights into a previously unrecognized effect of YAP on endothelial glycolysis and highlight the potential of targeting YAP/PFKFB3 axis in the treatment of ocular neovascularization.