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

Abstract

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 F2alpha (8-iso-PGF2alpha), 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-PGF2alpha secretion was increased. A selective COX-2 inhibitor decreased 8-iso-PGF2alpha 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-PGF2alpha 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-PGF2alpha 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-PGF2alpha, by activating TP receptors, participates in hypoxia-induced hyperreactivity of pulmonary arteries.

• Authors: Estelle Delannoy, Arnaud Courtois, Véronique Freund-Michel, Véronique Leblais, Roger Marthan, Bernard Muller
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 85 Issue 3 Pg. 582-92 (Feb 01 2010) ISSN: 1755-3245 [Electronic] England
• PMID: 19710084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoprostanes
• Receptors, Thromboxane
• Phenylephrine
• 8-epi-prostaglandin F2alpha
• Arachidonic Acid
• Dinoprost
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Animals
• Arachidonic Acid (pharmacology)
• Cyclooxygenase 2 (physiology)
• Dinoprost (analogs & derivatives, biosynthesis)
• Hypoxia (physiopathology)
• Isoprostanes (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Phenylephrine (pharmacology)
• Pulmonary Artery (physiopathology)
• Receptors, Thromboxane (physiology)
• Vasoconstriction (drug effects)