title: Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep.
abstract: Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR.
authors.affiliation: Division of Neonatology, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, USA. Paul.Rozance@ucdenver.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Rozance
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Seedorf
authors.forename: Alicia
authors.initials: A
authors.lastname: Brown
authors.forename: Gates
authors.initials: G
authors.lastname: Roe
authors.forename: Meghan C
authors.initials: MC
authors.lastname: O'Meara
authors.forename: Jason
authors.initials: J
authors.lastname: Gien
authors.forename: Jen-Ruey
authors.initials: JR
authors.lastname: Tang
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000473:pathology; D002449:Cell Aggregation; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology*; D005260:Female; D005317:Fetal Growth Retardation / Q000473:pathology* / Q000503:physiopathology; D015870:Gene Expression; D007328:Insulin / Q000494:pharmacology; D008168:Lung / Q000196:embryology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000196:embryology*; D011651:Pulmonary Artery / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology; D011972:Receptor, Insulin / Q000378:metabolism; D012756:Sheep / Q000196:embryology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D011972:Receptor, Insulin; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt