Cysteine Oxidation of Copper transporter SLC31A1/CTR1, drives VEGFR2 signaling and Angiogenesis

VEGFR2 (KDR/Flk1) signaling in endothelial cells (ECs) is essential for developmental and reparative angiogenesis. Reactive oxygen species (ROS) and copper (Cu) are also involved.in these processes. However, their inter-relationship is poorly understood. The role of endothelial Cu importer CTR1 in VEGFR2 signaling and angiogenesis in vivo is hitherto unknown. Here we show that CTR1 functions as a previously unrecognized redox sensor to promote angiogenesis in ECs. CTR1-depleted ECs showed reduced VEGF-induced VEGFR2 signaling and angiogenic responses. Mechanistically, CTR1 was rapidly sulfenylated at Cys189 in cytosolic C-terminus upon VEGF stimulation, which induced CTR1-VEGFR2 disulfide bond formation and their co-internalization to early endosomes, driving sustained VEGFR2 signaling. In vivo, EC-specific Ctr1-deficient mice or CRISPR/Cas9-generated “redox-dead” Cys to Ala Ctr1 knock-in mutant mice had impaired developmental and reparative angiogenesis. Thus, oxidation of CTR1 at Cys189 promotes VEGFR2 internalization and signaling to enhance angiogenesis. Our study uncovers an important mechanism for ROS sensing through CTR1 to drive neovascularization.