Hypoxia increases extracellular adenosine by shutting off the production of the adenosine transporter ENT1.

The body has evolved a variety of ways to limit the destructive effects of low oxygen, one of which is to ramp up extracellular levels of the nucleoside adenosine. High extracellular adenosine limits hypoxia-driven vascular leakage by promoting the barrier function of endothelial cells and helps dampen inflammatory responses by inhibiting immune cell activation and cytokine production. Now, on page 1493, Eltzschig and colleagues find that hypoxia keeps extracellular adenosine high by switching off production of its cellular importer.How the body accumulates extracellular adenosine, which is normally pumped rapidly back into cells by equilibrative nucleoside transporters (ENTs), is not completely clear. Hypoxia increases the expression of cell surface enzymes that hydrolyze ATP to adenosine and also increases the expression of adenosine receptors. But neither of these facts explains how extracellular adenosine avoids being rapidly shuttled back into cells by the ENT transporters.

Eltzschig and colleagues now show that hypoxia dampens the transcription of ENT1, which encodes the primary transporter of adenosine in endothelial cells, thereby decreasing the cell's adenosine importing capacity. The transcription factor HIF-1α (hypoxia inducible factor-1α) bound to the ENT1 promoter and was required for the repressive effect. The authors are now investigating how HIF-1α, best known for its ability to induce gene expression, shuts down the expression of ENT1.