Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells

Circulation. 2008 Apr 22;117(16):2114-22. doi: 10.1161/CIRCULATIONAHA.107.716241. Epub 2008 Apr 7.


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 I(2) analog, and prostaglandin E(2) 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 I(2) or prostaglandin E(2).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / physiology
  • Cells, Cultured
  • Chronic Disease
  • Collagen
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / pharmacology
  • Endothelin-1 / pharmacology
  • Gels
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / physiopathology*
  • Hypertrophy, Right Ventricular / metabolism
  • Hypertrophy, Right Ventricular / physiopathology
  • Hypoxia / metabolism
  • Hypoxia / physiopathology*
  • Iloprost / pharmacology
  • Mice
  • Mice, Mutant Strains
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / enzymology*
  • Pulmonary Artery / cytology
  • Pulmonary Artery / physiology
  • Receptor, Endothelin A / genetics
  • Traction
  • Vasoconstriction / drug effects
  • Vasoconstriction / physiology*
  • Vasodilator Agents / pharmacology


  • Endothelin-1
  • Gels
  • Receptor, Endothelin A
  • Vasodilator Agents
  • Collagen
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Iloprost
  • Dinoprostone