当前位置: X-MOL 学术Dev. Cell › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis
Developmental Cell ( IF 11.8 ) Pub Date : 2022-05-16 , DOI: 10.1016/j.devcel.2022.04.018
Roxana E Oberkersch 1 , Giovanna Pontarin 1 , Matteo Astone 1 , Marianna Spizzotin 1 , Liaisan Arslanbaeva 1 , Giovanni Tosi 1 , Emiliano Panieri 2 , Sara Ricciardi 3 , Maria Francesca Allega 4 , Alessia Brossa 2 , Paolo Grumati 5 , Benedetta Bussolati 2 , Stefano Biffo 3 , Saverio Tardito 4 , Massimo M Santoro 1
Affiliation  

Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.



中文翻译:

内皮细胞中的天冬氨酸代谢激活 mTORC1 通路以在血管生成过程中启动翻译

血管生成是从预先存在的血管中主动形成新血管,是一个复杂且要求很高的生物学过程,在生理和病理环境中都发挥着重要作用。最近的证据支持细胞代谢作为血管生成的关键调节剂。然而,细胞代谢是否以及如何调节内皮生长因子受体水平和核苷酸合成仍然难以捉摸。我们在人类细胞系和小鼠模型中显示,在发育和病理性血管生成过程中,内皮细胞 (EC) 使用谷氨酰胺分解衍生的谷氨酸通过天冬氨酸氨基转移酶 (AST/GOT) 产生天冬氨酸 (Asp)。Asp 导致 mTORC1 激活,进而调节 VEGFR2 和 FGFR1 合成的内皮翻译机制。Asp 依赖性 mTORC1 通路激活也调节血管生成内皮细胞中的从头嘧啶合成。这些发现将谷氨酰胺分解衍生的 Asp 确定为 mTORC1 依赖性内皮翻译和嘧啶合成的调节剂。我们的研究可能通过靶向内皮生长因子受体翻译来帮助克服抗 VEGF 治疗耐药性。

更新日期:2022-05-16
down
wechat
bug