Figure 1.

A. NO relaxes vascular smooth muscle (SMC) in part by redox regulation of SERCA. Nitrovasodilators activate guanylyl cyclase and increase cyclic GMP which activates protein kinase G (PKG), which in turn regulates its downstream targets to relax smooth muscle. Unlike guanylyl cyclase-dependent nitrovasodilators, authentic NO activates SERCA and refills intracellular Ca²⁺ stores. Consequently, store-operated cation channels (SOC) are inhibited and the decrease in intracellular free Ca²⁺ relaxes smooth muscle. The latter mechanism is predominantly cyclic-GMP-independent. B. Under physiological conditions (left) · NO and O₂^−• form the reactive nitrogen species, peroxynitrite (OONO⁻), which increases glutathione (GSH) adducts (GSS-) primarily on cysteine(C)-674 of SERCA. This adduct increases Ca²⁺ uptake activity of SERCA. Under pathophysiological conditions (right) higher levels of O₂^−• and H₂O₂ increase the destruction and consumption of · NO, and produce OONO⁻ which can irreversibly oxidize the reactive SERCA C674 thiol (-SO₃H). This prevents its reversible glutathiolation and blocks the stimulation of SERCA by · NO. Thus, the redox status of C674 can determine physiological and pathophysiological changes in vascular tone as well as SMC and endothelial cell (EC) migration. From reference [5].