sGC oxidation impairs NO-dependent ophthalmic artery vascular reactivity and alters long-term memory performance in mice

Nitric oxide (NO)-dependent activation of soluble guanylyl cyclase (sGC) is essential for maintaining cerebrovascular function and cognitive processes. However, sGC is susceptible to oxidative inactivation under vascular and neurodegenerative stress. This study investigated the impact of chronic sGC oxidation on ophthalmic artery (OphA) hemodynamics, brain cGMP signaling, and memory performance in vivo. Young adult C57BL/6 mice were treated for one month with the heme-oxidizing agent ODQ. Vascular responsiveness was assessed using Doppler flow velocity imaging. ODQ markedly blunted NO-dependent reductions in peak flow and end-diastolic velocity following sodium nitroprusside administration and altered pulsatility responses, demonstrating impaired NO-driven vascular reactivity. In contrast, the heme-independent sGC activator cinaciguat produced comparable hemodynamic responses in ODQ- and vehicle-treated mice, indicating preserved reactivity of oxidized or heme-deficient sGC. Biochemical assays of forebrain lysates revealed a significant reduction in NO-stimulated cGMP formation in forebrain tissue following ODQ treatment. Cinaciguat- and protoporphyrin IX–stimulated activities remained unchanged, consistent with a selective loss of NO sensitivity rather than reduced enzyme abundance; sGC protein levels remained stable across groups. Behaviorally, ODQ impaired long-term recognition memory, with significant post hoc deficits observed in male mice, whereas short-term spatial memory remained unaffected. These findings demonstrate that chronic sGC oxidation selectively disrupts NO-dependent vascular and sGC signaling while preserving responsiveness to heme-independent sGC activation. Because the efficacy of heme-independent sGC activators was maintained, these findings support their therapeutic potential for oxidative vascular and neurological disorders.