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

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 (ETA) in the lung after hypoxia. Similarly, selective pharmacological inhibition of COX-2 in wild-type mice exacer...