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(Circulation. 2008;117:2114-2122.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Absence of Cyclooxygenase-2 Exacerbates Hypoxia-Induced Pulmonary Hypertension and Enhances Contractility of Vascular Smooth Muscle Cells

Laura E. Fredenburgh, MD; Olin D. Liang, PhD; Alvaro A. Macias, MD; Thomas R. Polte, PhD; Xiaoli Liu, MD, PhD; Dario F. Riascos, MD; Su Wol Chung, PhD; Scott L. Schissel, MD, PhD; Donald E. Ingber, MD, PhD; S. Alex Mitsialis, PhD; Stella Kourembanas, MD; Mark A. Perrella, MD

From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital (L.E.F., A.A.M., X.L., D.F.R., S.W.C., S.L.S., M.A.P.), and Division of Newborn Medicine (O.D.L., S.A.M., S.K.) and Vascular Biology Program, Departments of Pathology and Surgery (T.R.P., D.E.I.), Children’s Hospital, Boston, Mass.

Correspondence to Mark A. Perrella, MD, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mperrella{at}rics.bwh.harvard.edu

Received May 18, 2007; accepted February 25, 2008.

Background— Cyclooxygenase-2 (COX-2) is upregulated in pulmonary artery smooth muscle cells (PASMCs) during hypoxia and may play a protective role in the response of the lung to hypoxia. Selective COX-2 inhibition may have detrimental pulmonary vascular consequences during hypoxia.

Methods and Results— To investigate the role of COX-2 in the pulmonary vascular response to hypoxia, we subjected wild-type and COX-2–deficient mice to a model of chronic normobaric hypoxia. COX-2–null mice developed severe pulmonary hypertension with exaggerated elevation of right ventricular systolic pressure, significant right ventricular hypertrophy, and striking vascular remodeling after hypoxia. Pulmonary vascular remodeling in COX-2–deficient mice was characterized by PASMC hypertrophy but not increased proliferation. Furthermore, COX-2–deficient mice had significant upregulation of the endothelin-1 receptor (ET_A) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ET_A receptor expression in pulmonary arterioles. The absence of COX-2 in vascular smooth muscle cells during hypoxia in vitro augmented traction forces and enhanced contractility of an extracellular matrix. Treatment of COX-2–deficient PASMCs with iloprost, a prostaglandin I₂ analog, and prostaglandin E₂ abrogated the potent contractile response to hypoxia and restored the wild-type phenotype.

Conclusions— Our findings reveal that hypoxia-induced pulmonary hypertension and vascular remodeling are exacerbated in the absence of COX-2 with enhanced ET_A receptor expression and increased PASMC hypertrophy. COX-2–deficient PASMCs have a maladaptive response to hypoxia manifested by exaggerated contractility, which may be rescued by either COX-2–derived prostaglandin I₂ or prostaglandin E₂.

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Clinical Summaries
Circulation 2008 117: 2041. [Full Text]