Division of Neonatology, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L860-71. doi: 10.1152/ajplung.00197.2011. Epub 2011 Aug 26.
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.
宫内生长受限 (IUGR) 会增加支气管肺发育不良 (BPD) 的风险。在 IUGR 的动物模型中已经注意到异常的肺结构，但 IUGR 是否会对胎儿肺血管发育和肺动脉内皮细胞 (PAEC) 功能产生不利影响尚不清楚。我们假设 IUGR 会降低胎儿肺肺泡化、血管生长和体外 PAEC 功能。这些研究是在一个已建立的严重胎盘功能不全模型中进行的，通过让怀孕的绵羊暴露在高温下来诱导 IUGR。IUGR 胎儿的肺泡化（通过径向肺泡计数来量化）减少了 20%（P < 0.005）。IUGR 胎儿的肺血管密度减少了 44%（P < 0.01）。在体外，胰岛素增加了对照 PAEC 的迁移、管形成和一氧化氮 (NO) 的产生。而这种反应在 IUGR PAEC 中是不存在的。VEGFA 刺激管形成，而 NO 的产生也不存在。在对照 PAEC 中，胰岛素使细胞生长增加了 68%（P < 0.0001）。IUGR PAEC 中的细胞生长在基线时减少了 29%（P < 0.01），对胰岛素的反应减弱（P < 0.005）。尽管 IUGR PAEC 中的 Akt 磷酸化增加，但内皮型一氧化氮合酶 (eNOS) 蛋白表达以及 eNOS 的基础和胰岛素刺激磷酸化均减少。VEGFA 和 VEGFR2 也在 IUGR PAEC 中减少。我们得出结论，患有 IUGR 的胎儿在体外表现为肺泡和血管生长减少以及 PAEC 功能障碍。这可能导致 IUGR 婴儿发生不良呼吸结局和 BPD 的风险增加。
