title: Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells.
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.
  
  
  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).
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Fredenburgh
authors.forename: Olin D
authors.initials: OD
authors.lastname: Liang
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Macias
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Polte
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Dario F
authors.initials: DF
authors.lastname: Riascos
authors.forename: Su Wol
authors.initials: SW
authors.lastname: Chung
authors.forename: Scott L
authors.initials: SL
authors.lastname: Schissel
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: S Alex
authors.initials: SA
authors.lastname: Mitsialis
authors.forename: Stella
authors.initials: S
authors.lastname: Kourembanas
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D003094:Collagen; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D005782:Gels; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D016285:Iloprost / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology; D044022:Receptor, Endothelin A / Q000235:genetics; D014143:Traction; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D005782:Gels; D044022:Receptor, Endothelin A; D014665:Vasodilator Agents; D003094:Collagen; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D016285:Iloprost; D015232:Dinoprostone