Early fetal hypoxia leads to growth restriction and myocardial thinning
Early fetal hypoxia leads to growth restriction and myocardial thinning
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DOI：
10.1152/ajpregu.00771.2007
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发表时间：
2008-08-01
影响因子：
2.8
通讯作者：
Chikaraishi, Dona M.
中科院分区：
文献类型：
--
作者：
Ream, Margie;Ray, Alisa M.;Chikaraishi, Dona M.
缺氧是胎儿发育所必需的；然而，过度缺氧是有害的。缺氧对近期胎儿的影响已被广泛研究，但对早期胎儿的影响知之甚少。本研究的目的是确定严重缺氧的易感窗口，哪些器官系统最敏感，以及缺氧胎儿死亡的原因。我们通过将母体吸入的O-2从21%降低到8%来诱导缺氧，这降低了吡咪唑结合评估的胎儿组织氧合。小鼠胎儿在妊娠中期最为脆弱：24 h缺氧导致胚胎期13.5天（E13.5）胎儿死亡89%，而E11.5天和E17.5天的胎儿死亡比例分别为5%和51%。E12.5时的亚致死性缺氧导致生长受限，胎儿体重减少26%，蛋白质减少45%。缺氧诱导HIF-1靶基因，包括血管内皮生长因子（Vegf）、促红细胞生成素、葡萄糖转运蛋白-1和胰岛素样生长因子结合蛋白-1 (Igfbp-1)，这些基因与人宫内生长限制（IUGR）有关。缺氧严重损害了心血管系统。18 - 24小时的缺氧可导致心衰，包括卵黄囊循环丧失、出血和水肿。缺氧诱导心室扩张和心肌发育不全，使心室组织减少50%，体外培养心脏减少21%，体外培养心脏减少40%。心外膜剥离是心脏缺氧损伤的第一个迹象，尽管心外膜来源的有丝分裂原，如FGF2、FGF9和Wnt9b的表达没有减少。我们认为缺氧通过心肌发育不全和心率降低对胎儿造成损害。
Hypoxia is necessary for fetal development; however, excess hypoxia is detrimental. Hypoxia has been extensively studied in the near-term fetus, but less is known about earlier fetal effects. The purpose of this study was to determine the window of vulnerability to severe hypoxia, what organ system(s) is most sensitive, and why hypoxic fetuses die. We induced hypoxia by reducing maternal-inspired O-2 from 21% to 8%, which decreased fetal tissue oxygenation assessed by pimonidazole binding. The mouse fetus was most vulnerable in midgestation: 24 h of hypoxia killed 89% of embryonic day 13.5 (E13.5) fetuses, but only 5% of E11.5 and 51% of E17.5 fetuses. Sublethal hypoxia at E12.5 caused growth restriction, reducing fetal weight by 26% and protein by 45%. Hypoxia induced HIF-1 target genes, including vascular endothelial growth factor (Vegf), erythropoietin, glucose transporter-1 and insulin-like growth factor binding protein-1 (Igfbp-1), which has been implicated in human intrauterine growth restriction ( IUGR). Hypoxia severely compromised the cardiovascular system. Signs of heart failure, including loss of yolk sac circulation, hemorrhage, and edema, were caused by 18 - 24 h of hypoxia. Hypoxia induced ventricular dilation and myocardial hypoplasia, decreasing ventricular tissue by 50% and proliferation by 21% in vivo and by 40% in isolated cultured hearts. Epicardial detachment was the first sign of hypoxic damage in the heart, although expression of epicardially derived mitogens, such as FGF2, FGF9, and Wnt9b was not reduced. We propose that hypoxia compromises the fetus through myocardial hypoplasia and reduced heart rate.