Cysteine oxidation of copper transporter CTR1 drives VEGFR2 signalling and angiogenesis

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. Das et al. show that the copper transporter CTR1 functions as a redox sensor in endothelial cells. CTR1 is modified after redox stress, which induces CTR1-VEGFR2 complex formation and promotes VEGFR2 signalling and angiogenesis.

Automated summary

This study uncovers an important role of the copper transporter CTR1 as a redox sensor in endothelial cells, promoting VEGFR2 signaling and angiogenesis. CTR1 undergoes modifications after redox stress, leading to the formation of CTR1-VEGFR2 complex and enhancing VEGFR2 signaling and angiogenesis.