The soluble epoxide hydrolase (sEH) is expressed in pulmonary artery smooth muscle cells where it metabolises lipid epoxides, including the epoxides of arachidonic acid (the epoxyeicosatrienoic acids; EETs), to their less active diols. We recently reported that the activity of the sEH is an important determinant of the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) as the enzyme inactivates vasoconstrictor EETs. Here we assessed the role of the sEH in the development of pulmonary hypertension and vascular remodelling in mice in response to hypoxia (10% O₂) for 21 days.

In wild-type mice, chronic hypoxia induced right heart hypertrophy and erythropoiesis, and increased the number of partially and fully muscularised pulmonary resistance arteries (by 3-fold). Furthermore, in isolated lungs, pre-exposure to chronic hypoxia increased baseline perfusion pressures and potentiated the acute HPV. While an sEH inhibitor potentiated acute HPV in lungs from mice maintained in normoxic conditions, it had no effect on HPV in lungs from mice exposed to hypoxia. The EET antagonist, 14,15-EEZE, abolished the sEH inhibitor-dependent increase in acute HPV in normoxic lungs and decreased HPV in chronic hypoxic lungs. Hypoxia-induced right heart hypertrophy and erythropoiesis were more pronounced in sEH-/- than in wild-type mice. Under normoxic and hypoxic conditions the muscularisation of resistance pulmonary arteries was greater in lungs from sEH-/- mice than in lungs from wild-type mice. sEH-/- mice also displayed an enhanced acute HPV, compared to that observed in wild-type mice and chronic exposure to hypoxia did not further potentiate acute HPV. In the presence of 14,15-EEZE responses returned to levels observed in normoxic lungs from wild-type animals. As hypoxia induced the same phenotype as sEH-deficiency we assessed the effects of hypoxia on enzyme expression and activity. In HEK293 cells hypoxia decreased sEH promoter activity. Furthermore, hypoxia decreased the pulmonary expression and activity of the sEH in isolated pulmonary smooth muscle cells as well as in vivo in intact lungs. Moreover, while the sEH was expressed in the medial wall of pulmonary arteries in lungs from healthy donors, we were unable to detect sEH protein in lung biopsies from patients with pulmonary hypertension.

Taken together these results indicate that a decrease in the expression and activity of the sEH is implicated in the development of chronic hypoxia-induced pulmonary hypertension and vascular remodelling.