Hypoxia-induced hyperreactivity of pulmonary arteries: role of cyclooxygenase-2, isoprostanes, and thromboxane receptors

Aims This study investigates the role of the cyclooxygenase (COX)/prostanoid pathway in chronic hypoxia-induced hyperreactivity of pulmonary arteries. Methods and results 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 A(2) (TXA(2))-synthase, release of TXA(2), prostacyclin (PGI(2)) and the isoprostane 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)), 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 TXA(2)-synthase was decreased. Chronic hypoxia differentially affected prostanoid release from pulmonary arteries: TXA(2) secretion was not significantly modified; PGI(2) secretion was decreased, whereas 8-iso-PGF(2 alpha) secretion was increased. A selective COX-2 inhibitor decreased 8-iso-PGF(2 alpha) 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 TXA(2)-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(2 alpha) induced a TP receptor-dependent contraction in pulmonary arteries and markedly potentiated the contractile response to PE. Conclusion Chronic hypoxia up-regulates COX-2 expression, increases 8-iso-PGF2a 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(2 alpha), by activating TP receptors, participates in hypoxia-induced hyperreactivity of pulmonary arteries.