The vasodilatory effect of sulfur dioxide via SGC/cGMP/PKG pathway in association with sulfhydryl-dependent dimerization. Am J Physiol Regul Integr Comp Physiol 310: R1073-R1080, 2016. First published March 23, 2016 doi:10.1152/ajpregu.00101.2015.-The present study was designed to explore the role of soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/PKG pathway in sulfur dioxide (SO 2)-induced vasodilation. We showed that SO2 induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted rat aortic rings in association with an increase in cGMP concentration, whereas L-aspartic acid -hydroxamate (HDX), an inhibitor of SO 2 synthase, contracted rings in a dose-dependent manner. Pretreatment of aortic rings with the sGC inhibitor ODQ (30 M) attenuated the vasodilatory effects of SO 2, suggesting the involvement of cGMP pathway in SO 2-induced vasodilation. Mechanistically, SO 2 upregulated the protein levels of sGC and PKG dimers, while HDX inhibited it, indicating SO 2 could promote cGMP synthesis through sGC activation. Furthermore, the dimerization of sGC and PKG and vasodilation induced by SO 2 in precontracted rings were significantly prevented by thiol reductants dithiothreitol (DTT). In addition, SO 2 reduced the activity of phosphodiesterase type 5 (PDE5), a cGMP-specific hydrolytic enzyme, implying that SO 2 elevated cGMP concentration by inhibiting its hydrolysis. Hence, SO2 exerted its vasodilatory effects at least partly by promoting disulfidedependent dimerization of sGC and PKG, resulting in an activated sGC/cGMP/PKG pathway in blood vessels. These findings revealed a new mode of action and mechanisms by which SO 2 regulated the vascular tone. sulfur dioxide; vasodilation; SGC; cGMP; PKG; dimer IN THE LAST DECADE, RESEARCH focusing on sulfur-containing amino acid metabolic pathways indicates that L-cysteine as a substrate cannot only generate hydrogen sulfide (H 2 S) through transsulfuration under cystathionine-␥-lyase or cystathionine-␥-synthase catalysis (35), but also endogenously generate sulfur dioxide (SO 2 ) under cysteine dioxygenase oxidation and aspartate aminotransferase (AAT) transamination (32). Recent studies have shown that endogenous SO 2 is generated in cardiovascular tissues, such as vascular endothelium, medial smooth muscles, right ventricle, and left ventricle (8). Similar to H 2 S, endogenous SO 2 has important physiological and pathophysiological roles, including hypotensive activity (4, 18), vasodilation (8, 9), inhibition of oxidative stress (3,28,48), inhibition of smooth muscle cell proliferation (17), and remodeling of pulmonary arterial endothelial cells (33), protection against myocardial ischemia/reperfusion (14,45,46), and isopropylarterenol-induced apoptosis (16). An increasing number of studies suggest that endogenous SO 2 is also a gaseous signaling molecule with a variety of cardiovascular functions, including vasodilation (24,44,26). Previous studies have shown that SO 2 could activate the calcium and potassium channels by i...