NO- and S-nitrosothiols-dependent relaxation in large and small resistance blood vessels

Nitric oxide (NO) has long been viewed as the principal endothelium-derived vasodilator through activation of soluble guanylyl cyclase (GC1) and cGMP-dependent signaling in vascular smooth muscle. However, accumulating evidence indicates that this canonical NO-GC1-cGMP pathway predominates in large conduit arteries, whereas regulation of vascular tone and blood pressure in the microcirculation relies largely on endothelium-derived hyperpolarization (EDH) with NO acting primarily as a redox signal rather than a freely diffusing gas. Here, we review emerging mechanisms that integrate NO-derived nitrosative signaling with EDH, highlighting the central role of protein S-nitrosation and transnitrosation in shaping endothelial excitability. A central focus of this review is the newly-identified endothelial role of GC1 beyond its canonical smooth muscle function. We summarize recent findings demonstrating that GC1 acts as a redox hub through S-nitrosation of a critical cysteine residue (cys), enabling selective transnitrosation of downstream targets that regulates endothelial Ca²⁺ influx, KCa channel activation, and EDH-dependent vasodilation independently of cGMP production. Finally, we examine how extravascular components-including perivascular adipose tissue and red blood cells-modulate EDH signaling under physiological and pathological conditions.