In this report, we provide evidence that vascular function of sGC is increased in GPSM1-deficient mice. We found that GPSM1-deficient mice have a lower resting blood pressure than their wild type counterparts. Intraperitoneal injection of sGC stimulator BAY 41-2272 elicited a transient decrease in blood pressure in both strains. However, GPSM1-/- mice were more sensitive to lower doses of BAY 41-2272, while the decrease in blood pressure was more profound and more sustained than in wild type mice. In ex vivo setting, preconstricted aortic rings from GPSM1-/- mice were more sensitive to acetylcholine and BAY 41-2272. Western blotting showed similar level of sGC expression in aortas of both strains. H&E staining of aorta sections showed no obvious morphologic differences between these strains of mice. However, aortas from GPSM1-/- mice sowed a higher level of cGMP accumulated in response to NO donor DEA-NO than from wild type animals. Unexpectedly, cGMP-degrading activity was also higher in GPSM1-/- mice. These data indicate that, at least in conductive vessels, sGC function is upregulated in the absence of GPSM1. These observations are consistent with previously observed GPSM1-dependent inhibition of sGC in cellular lysates.