Oxygen-dependent regulation of nNOS activity and vasomotor tone. (A) Hypoxia-induced transcription of an alternative nNOS mRNA species. The 2 panels depict nNOS mRNA transcription under normoxic (upper) and hypoxic (lower) conditions. In each panel, the mRNA transcription start site is indicated by a bent arrow; 5′-untranslated sequences are indicated by a light blue box; translated sequences are indicated by a dark blue box; intervening sequences are indicated by a thick line; and 5′-flanking sequences are indicated by a thin line. Top panel: Under normoxic conditions, transcription is initiated at exon 1 (red box), which consists of 5′-untranslated sequences. Exon 2 contains additional 5′-untranslated sequences (light blue box) and the beginning of the protein coding sequence (dark blue box). Lower panel: In this issue of the JCI, Ward et al. (9) demonstrate that under hypoxic conditions, transcription is initiated downstream of exon 1, resulting in the synthesis of nNOS mRNA containing an alternative 5′-untranslated region (light blue box). Under hypoxic conditions, the translation of mRNA containing exon 1 is inhibited, whereas the alternative mRNA is efficiently translated into protein. Thus, a qualitative change in the structure of nNOS mRNA based upon alternative transcription initiation results in a quantitative change in the levels of nNOS protein synthesized under hypoxic conditions. (B) Time-dependent responses to hypoxia in vascular smooth muscle cells. (C) Attenuation of physiological responses with chronic stimulation. A physiological stimulus (e.g., hypoxia) induces an acute physiological response (e.g., increased vascular tone). However, if the stimulus persists, the response is attenuated, resulting in the establishment of a new (reset) steady state.