血管生成
内化
细胞生物学
化学
新生血管
刺猬信号通路
体内
生物
信号转导
受体
生物化学
癌症研究
生物技术
作者
Archita Das,Dipankar Ash,Abdelrahman Y. Fouda,Sudhahar Varadarajan,Young-Mee Kim,Yali Hou,Farlyn Z. Hudson,Brian K. Stansfield,Ruth B. Caldwell,Malgorzata McMenamin,Rodney Littlejohn,Huabo Su,Meredith M. Regan,Bradley J. Merrill,Leslie B. Poole,Jack H. Kaplan,Tohru Fukai,Masuko Ushio‐Fukai
标识
DOI:10.1038/s41556-021-00822-7
摘要
Vascular endothelial growth factor receptor type 2 (VEGFR2, also known as KDR and FLK1) signalling in endothelial cells (ECs) is essential for developmental and reparative angiogenesis. Reactive oxygen species and copper (Cu) are also involved in these processes. However, their inter-relationship is poorly understood. Evidence of the role of the endothelial Cu importer CTR1 (also known as SLC31A1) in VEGFR2 signalling and angiogenesis in vivo is lacking. Here, we show that CTR1 functions as a redox sensor to promote angiogenesis in ECs. CTR1-depleted ECs showed reduced VEGF-induced VEGFR2 signalling and angiogenic responses. Mechanistically, CTR1 was rapidly sulfenylated at Cys189 at its cytosolic C terminus after stimulation with VEGF, which induced CTR1-VEGFR2 disulfide bond formation and their co-internalization to early endosomes, driving sustained VEGFR2 signalling. In vivo, EC-specific Ctr1-deficient mice or CRISPR-Cas9-generated redox-dead Ctr1(C187A)-knockin mutant mice had impaired developmental and reparative angiogenesis. Thus, oxidation of CTR1 at Cys189 promotes VEGFR2 internalization and signalling to enhance angiogenesis. Our study uncovers an important mechanism for sensing reactive oxygen species through CTR1 to drive neovascularization.
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