Figure 3.

Working model for the upregulation of endothelium-derived hyperpolarization during aging and development of chronic pathology per enhanced oxidative signaling. Cardiovascular aging and the development of chronic disease is associated with a progressive increase in endothelial oxidative signaling. Mitochondrial respiration is a primary source of superoxide (O₂^•−) which inactivates NO to peroxynitrite (ONOO⁻) and, via superoxide dismutase, O₂^•− is rapidly converted to H₂O₂. H₂O₂/OH^• activates SK_Ca and IK_Ca (primarily IK_Ca) channels directly and/or indirectly (Ca²⁺ influx through TRP channels). Thus, SK_Ca/IK_Ca channel function may “compensate” for decreased NO bioavailability to sustain local vasodilation. The (−) symbol indicates V_m hyperpolarization while the respective color of lines corresponds to O₂^•− (black), H₂O₂ (orange), or Ca²⁺ (red) signaling.