This study investigates the role of the cyclooxygenase (COX)/prostanoid pathway in chronic hypoxia-induced hyperreactivity of pulmonary arteries.

Pulmonary arteries were removed from normoxic or hypoxic (0.5 atm for 21 days) mice and studied for protein expression/localization of COX-1, COX-2, and thromboxane A₂ (TXA₂)-synthase, release of TXA₂, prostacyclin (PGI₂) and the isoprostane 8-iso-prostaglandin F_2α (8-iso-PGF_2α), and vasomotor responses. COX-2 expression was increased in all layers of pulmonary arteries from hypoxic mice. In contrast, COX-1 expression was not significantly modified following chronic hypoxia, whereas TXA₂-synthase was decreased. Chronic hypoxia differentially affected prostanoid release from pulmonary arteries: TXA₂ secretion was not significantly modified; PGI₂ secretion was decreased, whereas 8-iso-PGF_2α secretion was increased. A selective COX-2 inhibitor decreased 8-iso-PGF_2α release. Arachidonic acid elicited an endothelium- and COX-1-dependent relaxation in pulmonary arteries from normoxic mice. In contrast, arachidonic acid induced an endothelium-independent contraction in pulmonary arteries from hypoxic mice that was partially reduced by catalase, COX-1, COX-2, or TXA₂-synthase inhibitors and was totally abolished by blockade of the thromboxane (TP) receptor. Hyperresponsiveness to phenylephrine (PE) of pulmonary arteries from hypoxic mice was also decreased by COX-2 inhibitors, TP receptor antagonists or catalase, but not by TXA₂-synthase inhibitors. Finally, 8-iso-PGF_2α induced a TP receptor-dependent contraction in pulmonary arteries and markedly potentiated the contractile response to PE.

Chronic hypoxia up-regulates COX-2 expression, increases 8-iso-PGF_2α release, and shifts arachidonic acid-induced, endothelium-dependent relaxation to an endothelium-independent and TP receptor-dependent contraction in pulmonary arteries. COX-2-dependent production of 8-iso-PGF_2α, by activating TP receptors, participates in hypoxia-induced hyperreactivity of pulmonary arteries.