title: Altered prostanoid metabolism contributes to impaired angiogenesis in persistent pulmonary hypertension in a fetal lamb model.
abstract: BACKGROUND
  Persistent pulmonary hypertension of the newborn (PPHN) is associated with decreased lung angiogenesis and impaired pulmonary vasodilatation at birth. Prostanoids are important modulators of vascular tone and angiogenesis. We hypothesized that altered levels of prostacyclin (PGI₂), a potent vasodilator, and thromboxane A₂ (TXA₂), a vasoconstrictor, contribute to impaired angiogenesis of pulmonary artery endothelial cells (PAEC) in PPHN.
  
  
  METHODS
  PAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction or from sham operated controls. Expression and activity of PGI₂ synthase (PGIS) and TXA₂ synthase (TXAS), expression of cyclooxygenases 1 and 2 (COX-1 and COX-2), and the role of PGIS/TXAS alterations in angiogenesis were investigated in PAEC from PPHN and control lambs.
  
  
  RESULTS
  PGIS protein and activity were decreased and PGIS protein tyrosine nitration was increased in PPHN PAEC. In contrast, TXAS protein and its stimulated activity were increased in PPHN PAEC. COX-1 and COX-2 proteins were decreased in PPHN PAEC. Addition of PGI₂ improved in vitro tube formation by PPHN PAEC, whereas indomethacin decreased tube formation by control PAEC. PGIS knockdown decreased the in vitro angiogenesis in control PAEC, whereas TXAS knockdown increased the in vitro angiogenesis in PPHN PAEC.
  
  
  CONCLUSIONS
  Reciprocal alterations in PGI₂ and TXA₂ may contribute to impaired angiogenesis in PPHN.
authors.affiliation: Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Chaitali N
authors.initials: CN
authors.lastname: Mahajan
authors.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Adeleye J
authors.initials: AJ
authors.lastname: Afolayan
authors.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Annie
authors.initials: A
authors.lastname: Eis
authors.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ru-Jeng
authors.initials: RJ
authors.lastname: Teng
authors.affiliation: Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Girija G
authors.initials: GG
authors.lastname: Konduri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D005333:Fetus; D055785:Gene Knockdown Techniques; D047468:Immunoprecipitation; D007213:Indomethacin; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010547:Persistent Fetal Circulation Syndrome / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000166:cytology*; D012756:Sheep; D018709:Statistics, Nonparametric; D013928:Thromboxane A2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000378:metabolism
chemical_list: D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D013930:Thromboxane-A Synthase; D007213:Indomethacin