Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep
Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep
复制标题
DOI：
10.1152/ajplung.00197.2011
复制
发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Abman, Steven H.
中科院分区：
文献类型：
--
作者：
Rozance, Paul J.;Seedorf, Gregory J.;Abman, Steven H.
Rozance PJ, Seedorf GJ, Brown A, Roe G， O'Meara MC, Gien J, Tang J, Abman SH.宫内生长限制对胎羊肺泡和血管生长的影响及体外肺动脉内皮细胞功能障碍。[J] .中国生物医学工程学报，2016,31(2):387 - 398。首次发表于2011年8月26日；doi: 10.1152 / ajplung.00197.2011。-宫内生长受限（IUGR）增加支气管肺发育不良（BPD）的风险。在IUGR动物模型中发现了肺结构异常，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会降低胎儿肺泡化、血管生长和体外PAEC功能。研究是在一个已建立的模型中进行的，该模型是由将怀孕的绵羊暴露在高温下引起的严重胎盘功能不全和IUGR。通过径向肺泡计数量化的肺泡化，IUGR胎儿的肺泡化减少了20% （P < 0.005）。IUGR胎儿肺血管密度降低44% （P < 0.01）。在体外，胰岛素增加了PAEC的迁移、管的形成和一氧化氮（NO）的产生。IUGR paec中没有这种反应。VEGFA刺激了试管的形成，也没有产生NO。在对照PAECs中，胰岛素使细胞生长增加68% （P < 0.0001）。IUGR PAECs的细胞生长在基线时减少29% (P < 0.01)，对胰岛素的反应减弱（P < 0.005）。尽管IUGR PAECs中基础和胰岛素刺激的Akt磷酸化增加，但IUGR PAECs中内皮NO合成酶（eNOS）蛋白表达以及基础和胰岛素刺激的eNOS磷酸化均降低。IUGR PAECs中VEGFA和VEGFR2也均降低。我们得出结论，IUGR胎儿的特征是肺泡和血管生长减少以及PAEC体外功能障碍。这可能会增加IUGR婴儿发生不良呼吸结局和BPD的风险。
Rozance PJ, Seedorf GJ, Brown A, Roe G, O'Meara MC, Gien J, Tang J, Abman SH. Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep. Am J Physiol Lung Cell Mol Physiol 301: L860-L871, 2011. First published August 26, 2011; doi: 10.1152/ajplung.00197.2011.-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.