Abstract
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 exacerbated hypoxia-induced pulmonary hypertension and resulted in PASMC hypertrophy and increased ETA 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 ETA 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.
Original language | English (US) |
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Pages (from-to) | 2114-2122 |
Number of pages | 9 |
Journal | Circulation |
Volume | 117 |
Issue number | 16 |
DOIs | |
State | Published - Apr 2008 |
Externally published | Yes |
Keywords
- Hypertension, pulmonary
- Hypertrophy
- Hypoxia
- Prostaglandins
- Remodeling
- Vasculature
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)