Hydrogen sulfide regulates the redox state of soluble guanylate cyclase in CSE-/- mice corpus cavernosum microcirculation

The corpus cavernosum (CC) is a highly vascularized tissue and represents an excellent example of microcirculation. Indeed, erectile dysfunction is considered an early index of cardiovascular disease. Hydrogen sulfide (H₂S) at the vascular level is endogenously produced from L-cysteine mainly by the action of cystathionine-γ-lyase (CSE) and plays a role in CC vascular homeostasis. Here we have evaluated the involvement of the endogenous H₂S in the regulation of the soluble guanylate cyclase (sCG) redox state. The lack of CSE-derived endogenous H₂S, in CSE^-/- mice, disrupted the eNOS/NO/sGC/PDE pathway. Indeed, the absence of CSE-derived endogenous H₂S caused a significant reduction of the relaxant response to riociguat, an sGC redox-dependent stimulator. Conversely, the response to cinaciguat, an sGC redox-independent activator, was not modified. The relevance of the role played at the redox level of the endogenous H₂S was confirmed by the findings that in CC harvested from CSE^-/- mice there was a significant reduction of GC_β1 expression coupled with a decrease in CYP5R3, a reductase involved in the regulation of the redox state of sGC. These molecular changes driven by the lack of endogenous H₂S translate into a significant reduction in cGMP levels. The replenishment of the lack of H₂S with an H₂S donor rescued the relaxant response to riociguat in CC of CSE^-/- mice. In conclusion, the endogenous CSE-derived H₂S plays a physiological key role in the regulation of the redox state of sGC in CC microcirculation.