Transcriptional control of purinergic signaling during ischemia and reperfusion. As part of ischemia and reperfusion injury (as shown here for intestinal ischemia and reperfusion injury), ischemic organs become severely hypoxic (eg, in the intestinal mucosa). Hypoxia results in the stabilization of hypoxia-dependent transcription factors, which in turn have a major effect on purinergic signaling events. For example, hypoxia-elicited activation of SP1 and subsequent binding of SP1 to the promoter of CD39 is associated with the transcriptional induction of CD39 expression and enzymatic activity. Similarly, hypoxia causes stabilization of the hypoxia-inducible transcription factor HIF, and binding of HIF to the promoter of CD73 promotes the transcriptional induction of CD73 transcript, protein, and enzyme activity. This coordinated response enhances the increased conversion of extracellular nucleotides (eg, ATP) to adenosine. Similarly, adenosine signaling events through adenosine receptors, for example the Adora2b (A2B) expressed on intestinal epithelial cells and the Adora2a (A2A) expressed on inflammatory cells, are increased by HIF. Together, these transcriptional alterations and concomitant changes in purinergic signaling are critical in attenuating inflammation and promoting ischemia tolerance during ischemia and reperfusion injury.