Proteomic studies allowed us to identify PKA RIα and then PKG Iα as kinases that form interprotein disulfides in response to oxidants such as hydrogen peroxide (H2O2). This oxidation event directly activated PKG Iα independently of the classical NO-cGMP pathway to cause vasodilation. Subsequently we generated a Cys42Ser PKG Iα ‘redox-dead’ knock-in (KI) mouse. PKG Iα in these KI mice cannot be oxidant-activated as it lacks the thiol redox sensor. Consequently KI blood vessels do not relax fully to oxidants or endothelium derived hyperpolarising factor (EDHF) stimuli - resulting in hypertension in vivo compared to wild-type (WT) littermates. This provided robust evidence PKG Iα oxidation is a significant mechanism of lowering BP in vivo. Additional studies showed cGMP binding to PKG induces a state that is resistant to disulfide formation. Thus interventions that lower cGMP stimulate PKG oxidation. Consequently, PKG oxidation occurs to a lesser extent in aortas than in mesenteries, as conduit vessels have higher levels of NO. Conduit vessels also express more peroxiredoxin and thioredoxin than resistance vessels, perhaps allowing oxidants such as H2O2 accumulate at higher levels in the latter. Together this helps explain why resistance vessels, principal regulators of blood pressure, are highly sensitive to PKG Iα oxidation and consequently oxidant-induced vasodilation compared to conduits.