O 2 is essential for aerobic life, and the classic view is that it diffuses freely across the plasma membrane. However, measurements of O 2 permeability of lipid bilayers have indicated that it is much lower than previously thought, and therefore, the existence of membrane O 2 channels has been suggested. We hypothesized that, besides its role as a water channel, aquaporin-1 (AQP-1) could also work as an O 2 transporter, because this transmembrane protein appears to be CO 2 -permeable and is highly expressed in cells with rapid O 2 turnover (erythrocytes and microvessel endothelium). Here we show that in mammalian cells overexpressing AQP-1 and exposed to hypoxia, the loss of cytosolic O 2 , as well as stabilization of the O 2 -dependent hypoxia-inducible transcription factor and expression of its target genes, is accelerated. In normoxic endothelial cells, knocking down AQP-1 produces induction of hypoxiainducible genes. Moreover, lung AQP-1 is markedly up-regulated in animals exposed to hypoxia. These data suggest that AQP-1 has O 2 permeability and thus could facilitate O 2 diffusion across the cell membrane.Oxygen (O 2 ) is necessary for aerobic life because of its central role in mitochondrial ATP synthesis by oxidative phosphorylation. Traditionally, O 2 is considered to diffuse freely across the plasma membrane (1, 2); however, recent studies have shown that O 2 permeability of lipid bilayers is some orders of magnitude lower than previously thought (3). Therefore, it has been suggested that there exist yet unknown plasmalemmal O 2 channels to ensure the fluxes required for O 2 uptake in conditions of high demand or limited O 2 availability. Good candidates are aquaporins, widely distributed intrinsic membrane proteins that form water-permeable complexes (3, 4). Mammalian aquaporin-1 (AQP-1) 4 is highly expressed in cells with rapid gas (O 2 /CO 2 ) turnover such as erythrocytes (5) and microvessel endothelium (6, 7), and experiments performed with recombinant AQP-1 expressed in Xenopus oocytes have suggested that it confers upon the cells increased membrane CO 2 permeability (8 -10). In addition, it has been shown that the AQP-1 tobacco plant homolog Nt-AQP-1 facilitates CO 2 transport, particularly in conditions of small transmembrane CO 2 gradient, and has a significant function in photosynthesis and in stomatal opening (11). Against a possible role of AQP-1 as a gas channel is that AQP-1 null mice do not show any obvious sign of respiratory distress or alteration of lung or erythrocyte CO 2 transport (12, 13). This observation could, however, be explained if other aquaporins can compensate, at least partially, for the lack of AQP-1. In fact, AQP-1 functions as a well established water channel, but AQP-1 null humans (Colton-null blood group) (14) and AQP-1-deficient mice (12) have only subtle changes of erythrocyte water diffusion or renal urine concentration. A recent study shows that after subcutaneous or intracranial malignant cell implantation, AQP-1 null animals present impaired tumor growth and v...

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