1. We have previously reported that the inhibitory gamma subunit of the rod photoreceptor type 6 cyclic GMP phosphodiesterase (PDEgamma) is expressed in nonretinal tissues and is involved in the stimulation of the p42/p44 mitogen-activated protein kinase (MAPK) pathway by growth factors and G-protein-coupled receptor agonists. We have now investigated whether PDEgamma plays a role in modulating chronic hypoxic-dependent mitogenic signalling pathways in pulmonary smooth muscle from rats with pulmonary hypertension (PHT). 2. We show for the first time that PDEgamma is expressed in rat main, first, intrapulmonary and resistance pulmonary arteries. Moreover, its expression is increased in all the arteries to varying extents by chronic hypoxia. The extent of the increased expression of PDEgamma is correlated with an enhanced activation of p42/p44 MAPK in these vessels. 3. We also report that PDEgamma translation from mRNA transcript is increased in cultured human pulmonary artery smooth muscle cells subjected to chronic hypoxia for 14 days. This was correlated with hypoxic-dependent increase in p42/p44 MAPK activation. 4. In conclusion, our studies identify for the first time a major chronic hypoxic-dependent change in the phenotypic expression of an intermediate protein regulating mitogenic signalling in pulmonary arteries. This may have a significant effect on arterial remodelling in PHT. Future studies will focus on strategies designed to knockout rod PDEgamma to assess whether this rescues rats from chronic hypoxic-dependent changes in arterial remodelling and PHT.