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An important physiological response to changes in local or systemic oxygenation is the modulation of vascular tone, which is mediated in part by changes in the activities of the 3 NO synthase (NOS) isoforms. In arterial smooth muscle cells, acute hypoxia induces increased vascular tone, which is attenuated if hypoxia persists. In this issue of the JCI, Ward et al. demonstrate that changes in O2 concentration have effects on neuronal NOS enzymatic activity and gene expression that contribute to vascular homeostasis under conditions of acute and chronic hypoxia.