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Cardiovascular Research Advance Access first published online on August 26, 2009
This version [Corrected Proof] published online on September 16, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp292
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

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

Estelle Delannoy1,2,3, Arnaud Courtois1,2, Véronique Freund-Michel1,2, Véronique Leblais1,2, Roger Marthan1,2,3 and Bernard Muller1,2,*

1 Université Bordeaux 2, Bordeaux F-33076, France
2 INSERM U885, 146, rue Léo Saignat (casier 83), Bordeaux F-33076, France
3 CHU de Bordeaux, Bordeaux F-33076, France

* Corresponding author. Tel: +33 557 571 212, Fax: +33 557 571 201, Email: bernard.muller{at}u-bordeaux2.fr

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 A2 (TXA2)-synthase, release of TXA2, prostacyclin (PGI2) and the isoprostane 8-iso-prostaglandin F2{alpha} (8-iso-PGF2{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 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-PGF2{alpha} secretion was increased. A selective COX-2 inhibitor decreased 8-iso-PGF2{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 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-PGF2{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-PGF2{alpha} 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-PGF2{alpha}, by activating TP receptors, participates in hypoxia-induced hyperreactivity of pulmonary arteries.

KEYWORDS Chronic hypoxia; Pulmonary arteries; Cyclooxygenase-2; Isoprostanes; TP receptors

Time for primary review: 16 days


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