Figure 6.

A schematic of the proposed mechanisms underlying the vasodilation induced by the mitochondrial depolarization in the endothelium. Depolarization of mitochondria leads to elevation of endothelial [Ca²⁺]_i by both reactive oxygen species (ROS)-dependent and independent mechanisms. Elevation of global endothelial [Ca²⁺]_i promotes activation of endothelial NO synthase (eNOS) which in turn leads to generation of nitric oxide (NO). Mitochondrial depolarization in endothelial cells also promotes activation of phosphoinositide 3 kinase (PI3K), phosphorylation of Akt, and subsequently phosphorylation of eNOS resulting in [Ca²⁺]_i independent activation of eNOS leading to NO generation. Finally, mitochondrial-depolarization-induced endothelium-dependent vasodilation is primarily mediated by NO and this effect enhances VSM-specific relaxation. Mitochondrial depolarization in vascular smooth muscle cells sequentially causes the activation of ryanodine-sensitive Ca²⁺ channels on sarcoplasmic reticulum, generation of calcium transients, ‘calcium sparks’, and the opening of adjacent large-conductance calcium activated potassium channels (BK_Ca) on the plasma membrane. The efflux of K⁺ thus leads to hyperpolarization, decreased global intracellular Ca²⁺ of smooth muscle, and vasodilation.