Phases of adenosine signaling that occur during ischemia and reperfusion. Tissue ischemia and hypoxia acutely stimulate the production of adenosine from intracellular sources. ATP that is released from endothelial cells (ECs) in response to shear stress and by other stimuli is converted to ADP/AMP by the ectoenzyme CD39 (NTPDase1). AMP is converted to adenosine (ADO) by CD73, also on the EC surface. ADO limits the extent of acute inflammation by activating anti-inflammatory A_2A and A_2B receptors on macrophages, neutrophils, lymphocytes, and ECs.¹,^-5,Beginning 2 to 4 hours after hypoxia, hypoxia-inducible factor-induced transcription of adenosine A_2B receptors, CD39, and CD73 on ECs stimulates enhanced adenosine production and signaling.⁶,Adenosine levels also are increased following hypoxia by transcriptional repression of equilibrative nucleoside transporters (ENTs).⁷ Subsequently, adenosine levels decline in association with accelerated extravasation of activated macrophages that remove necrotic debris. Eltzschig and colleagues show that a late decline in adenosine may occur in part from induction of ADA and CD26. Declining adenosine may also result from the cleavage of CD39 from the EC surface following ischemia-reperfusion injury.⁸