Hypoxia or metabolic stress diminishes CK and increases AK flux, inducing AMP generation and subsequent AMP/adenosine signaling events. Adenosine/AMP signals delivered to vascular tissue through intercellular and para-cellular pathways induce signaling through adenosine receptors A(2A)AR, AMPKα1, and KATP channels. AMPKα1 activates eNOS, inducing NO/cGMP signaling, and could regulate KATP channels. Collectively, A(2A)AR, AMPKα1, eNOS, and KATP signaling converge on contractile protein, Ca2+, and membrane potential regulation, critical determinants of vascular tone.