title: Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension.
abstract: BACKGROUND
  Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased risk of neuro-developmental impairments. Whether relative fetal hypoxia during evolution of PPHN renders the fetal brain vulnerable to perinatal brain injury remains unclear. We hypothesized that in utero ductal constriction, which induces PPHN also impairs cerebral angiogenesis.
  
  
  METHODS
  Fetal lambs with PPHN induced by prenatal ligation of the ductus arteriosus were compared to gestation matched twin controls. Freshly collected or fixed brain specimens were analyzed by immunohistochemistry, Western blot analysis, and RT-PCR.
  
  
  RESULTS
  Cortical capillary density was decreased in PPHN lambs compared to controls (Glut-1, isolectin B-4 and factor VIII, n=6, p<0.05). Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels were decreased in cortical cell lysates of PPHN lambs. PPHN increased angiopoetin-1 (Ang-1) and tyrosine-protein kinase receptor (Tie-2) protein expression while angiopoetin-2 (Ang-2) protein levels were decreased (n=6, p<0.05). PPHN did not change mRNA levels of these proteins significantly (n=6).
  
  
  CONCLUSIONS
  PPHN decreased cortical capillary density in fetal lamb brain. PPHN decreased the expression of proteins involved in angiogenesis. These findings suggest that PPHN is associated with impaired cortical angiogenesis.
authors.affiliation: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Wauwatosa, WI 53226, USA. Electronic address: scohen@mcw.edu.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Wauwatosa, WI 53226, USA.
authors.forename: Bethany R
authors.initials: BR
authors.lastname: Powers
authors.affiliation: Department of Pathology, Division of Pediatric Pathology, Medical College of Wisconsin, Wauwatosa, WI 53226, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lerch-Gaggl
authors.affiliation: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Wauwatosa, WI 53226, USA.
authors.forename: Ru-Jeng
authors.initials: RJ
authors.lastname: Teng
authors.affiliation: Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin, Wauwatosa, WI 53226, USA.
authors.forename: Girija Ganesh
authors.initials: GG
authors.lastname: Konduri
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010547:Persistent Fetal Circulation Syndrome / Q000150:complications* / Q000473:pathology*; D011247:Pregnancy; D034561:Sheep, Domestic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2
keywords: HIF-1α; VEGF; cerebral angiogenesis; persistent pulmonary hypertension in the newborn (PPHN); sheep