An overview of EMS. EMS consists of three key stages (top) for which example inputs and outputs are given for an idealized tissue. This basic framework can be applied to study EMS in different organ systems, but the molecules underlying initiation and transduction may vary. EMS is first initiated by metabolic activity which causes a decrease in the availability of extracellular substrates and/or changes in intracellular energy status and an increase in metabolic byproducts. In the second stage of EMS, this metabolic disturbance is sensed by the local vasculature and rapidly transduced into endothelial cell membrane hyperpolarization via an increase in K⁺ channel activity, which will ultimately promote vasodilation and an increase in blood flow. Hyperpolarizing signals are initiated in capillaries at the nexus of metabolic activity where capillary pericytes and endothelial cells play key roles in this process and are transmitted either by passive electrotonic spread or by regenerative Kir2.1-mediated signaling upstream to areas of the vasculature covered in contractile cells (i.e., contractile pericytes or smooth muscle cells). These contractile cells are induced to relax to produce an increase in blood flow, and this final output of EMS delivers more substrates to the active region and has the effect of reversing the deviations from set-point of the initiating metabolic factors and homeostatically resets local metabolic reserves.