Hydropersulfides promote angiogenesis and preserve vascular function.

Hydropersulfides (RSSH) are increasingly recognized as key mediators in redox signalling in mammalian cells, although their physiological functions, especially in angiogenesis, remain unknown. Direct mechanistic investigation of RSSH has been challenging due to their instability and high reactivity. To address this, donors that release RSSH in a controlled manner have been developed, enabling investigation of its biological roles. Herein, we employed thiol- and enzyme-activated RSSH donors along with mutant mouse models deficient in the Cys-SSH-producing enzyme cysteinyl-tRNA synthetase/cysteine persulfide synthase (CARS2/CPERS), to examine their role in vascular angiogenesis. We demonstrate that RSSH promotes angiogenesis via the CARS2/CPERS signalling axis and activation of the Akt-eNOS and NO-cGMP pathway. We also demonstrate that nitric oxide (NO) signalling in resistance vessels requires an intact CARS2/CPER2 pathway. These findings suggest that RSSH plays an important role in regulating angiogenesis and vascular tone.