Sensory neurons of rat and mice dorsal root ganglia respond to hypoxia with increased NO generation.

Abstract

Studies on Drosophila larvae have added nitric oxide (NO) as another endogenous intracellular signalling molecule mediating hypoxia-induced adaptations (Wingrove and O'Farrell, 1999; DiGregorio et al. 2001). In mammalian cells, exogenously applied NO is able to interfere with the signalling cascades that are activated by low oxygen tension. NO treatment under normoxic conditions stabilizes hypoxia-inducible factor-la (HIF-la), the major transcription factor involved in hypoxia-regulated gene expression, and promotes its DNA-binding activity and downstream gene expression (Genius and Fandrey, 2000; Kimura et al. 2000; Palmer et al., 2000; Sandau et al. 2001). It is currently unclear, whether this effect is due to an interaction of NO with the iron containing HIF-modulating enzyme, HIF- prolyl-hydroxylase (Ivan et al. 2001; Jaakkola et al. 2001) or whether NO acts via a different pathway. Under hypoxic conditions, however, partly opposing effects of exogenously applied NO have been reported (Liu et al. 1998; Huang et al. 1999; Sogawa et al. 1998). One possible explanation is that NO may react with ROS formed during hypoxia to yield compounds such as peroxynitrite that do not stimulate HIF-la (Semenza, 2001). Similarly, the effect of NO on the skeletal muscle calcium release channel is critically dependent on pO2 (Eu et al. 2000). None of these studies reported on the endogenous production of NO under these conditions.