Resistance vessels controlling skeletal muscle blood flow are arranged in series and in parallel. Thus vasodilation must be coordinated among parent and daughter branches of vascular resistance networks to effectively control the magnitude and distribution of muscle blood flow during exercise. Dilation of terminal arterioles controlling capillary perfusion has little effect on local blood flow if upstream branches remain constricted. Further, at bifurcations, dilation of one daughter branch can ‘steal’ flow from its sister branch if the parent vessel does not dilate in concert. Because the fibers of individual motor units are dispersed within a muscle, vasoactive signals arising from discrete locations must be integrated by arteriolar networks to effectively increase oxygen delivery according to local metabolic demand. As contractile activity increases, vasodilation originating in downstream arterioles ‘ascends’ to encompass upstream arterioles and feed arteries, thereby increasing local perfusion. As we have observed with intravital microscopy and substantiated using intracellular recording with fluorescent markers, the ability of parent vessels to respond in such a coordinated manner reflects cell-to-cell electrical signaling through gap junction channels (GJCs). These protein complexes form intercellular channels that electrically couple neighboring endothelial cells (ECs) to each other along the intima. Further, myoendothelial GJCs couple the endothelium with surrounding smooth muscle cells (SMCs). Thus electrical signals (e.g., hyperpolarization) initiated at distinct sites can spread rapidly along the endothelium to coordinate vasodilation along and among branches of vascular resistance networks. The regulation of spreading vasodilation has centered on the role and modification of GJCs. We questioned whether an alternative mechanism could govern electrical signaling along the vessel wall. Small- and intermediate conductance Ca2+-activated K+ channels (SKCa/IKCa; KCa2.3/KCa3.1) are highly expressed in the plasma membrane of ECs. We therefore tested whether activation of these voltage-insensitive ion channels could inhibit electrical conduction by ‘leaking’ current through EC membranes. Intact endothelial tubes were freshly isolated from mouse skeletal muscle feed arteries for Ca2+ imaging and for intracellular recording during current microinjection. Remarkably, activating SKCa/IKCa channels (selectively with NS309 or indirectly with acetylcholine via intracellular Ca2+) inhibited electrical conduction. At the same time dye transfer between ECs confirmed that GJCs remained intact. Thus loss of current through open SKCa/IKCa channels effectively dissipated electrical signals along the endothelium independent of GJCs. In a reciprocal manner, inhibiting SKCa/IKCa channels (with apamin + charybdotoxin) enhanced intercellular electrical conduction by reducing current loss through EC membranes. Aging is associated with elevated sympathetic nerve activity (SNA) and oxidative stress. In the gluteus maximus muscle of Old (~2 years) versus Young (~4 months) male C57BL/6 mice, enhanced activation of α-adrenoreceptors on SMCs effectively restricted muscle blood flow at rest and during contractile activity. Independent of SMCs, electrical conduction along endothelial tubes from Old (vs. Young) mice is impaired. Our recent findings explain this difference through revealing enhanced SKCa/IKCa channel activation by reactive oxygen species (ROS). Thus, with aging, the actions of SNA on vascular smooth muscle and of ROS on the endothelium work together to impair spreading vasodilation, restrict muscle blood flow and limit skeletal muscle function. Vascular disease and obesity are commonly associated with elevated SNA, oxidative stress and impaired muscle blood flow along with diminished physical activity. Our studies of the microcirculation focus on providing mechanistic insight towards the development of appropriate and effective therapeutic interventions to improve tissue perfusion and maintain the quality of life for aging populations and for individuals affected by vascular disease.