Published Online
on October 18, 2004

A more recent version of this article appeared on October 26, 2004

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Submitted on September 18, 2003
Revised on June 16, 2004
Accepted on June 17, 2004

Intravascular Thrombosis After Hypoxia-Induced Pulmonary Hypertension. Regulation by Cyclooxygenase-2

Graham P. Pidgeon PhD^*, Rasa Tamosiuniene MD, Gang Chen PhD, Irene Leonard MD, Orina Belton PhD, Aidan Bradford PhD, and Desmond J. Fitzgerald MD

From the Departments of Clinical Pharmacology (G.P.P., R.T., I.L., O.B., D.J.F.), Surgery (G.C.), and Physiology (A.B.), Royal College of Surgeons Ireland, Dublin, Ireland.

^* To whom correspondence should be addressed. E-mail: gpidgeon{at}rcsi.ie.

Background--Pulmonary hypertension induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Prostacyclin analogues reduce pulmonary pressures in this condition; raising the possibility that cycloxygenase-2 (COX-2) modulates the response of the pulmonary vasculature to hypoxia.

Methods and Results--Sprague-Dawley rats in which pulmonary hypertension was induced by hypobaric hypoxia for 14 days were treated concurrently with the selective COX-2 inhibitor SC236 or vehicle. Mean pulmonary arterial pressure (mPAP) was elevated after hypoxia (28.1±3.2 versus 17.2±3.1 mm Hg; n=8, P<0.01), with thickening of small pulmonary arteries and increased COX-2 expression and prostacyclin formation. Selective inhibition of COX-2 aggravated the increase in mPAP (42.8±5.9 mm Hg; n=8, P<0.05), an effect that was attenuated by the thromboxane (TX) A₂/prostaglandin endoperoxide receptor antagonist ifetroban. Urinary TXB₂ increased during hypoxia (5.9±0.9 versus 1.2±0.2 ng/mg creatinine; n=6, P<0.01) and was further increased by COX-2 inhibition (8.5±0.7 ng/mg creatinine; n=6, P<0.05). In contrast, urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F₁ decreased with COX-2 inhibition (8.6±3.0 versus 27.0±4.8 ng/mg creatinine; n=6, P<0.05). Platelet activation was enhanced after chronic hypoxia. COX-2 inhibition further reduced the PFA-100 closure time and enhanced platelet deposition in the smaller pulmonary arteries, effects that were attenuated by ifetroban. Mice with targeted disruption of the COX-2 gene exposed to chronic hypoxia had exacerbated right ventricular end-systolic pressure, whereas targeted disruption of COX-1 had no effect.

Conclusions--COX-2 expression is increased and regulates platelet activity and intravascular thrombosis in hypoxia-induced pulmonary hypertension.

Key words: thrombosis • hypoxia • hypertension, pulmonary • prostaglandins

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