Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, Tohoku, Japan.
Hypertens Res. 2019 Jan;42(1):29-39. doi: 10.1038/s41440-018-0092-7. Epub 2018 Sep 13.
Recently, advanced maternal age (AMA) has increased in Western countries because of late marriage and advances in assisted reproductive technology. One major complication of AMA is hypertensive disorders of pregnancy (HDP). While clinical investigations into human AMA have been reported, there has been limited information obtained from basic research. In this investigation, we established the AMA mouse model using aged pregnant ICR mice. We demonstrated that the phenotypes of aged pregnant ICR mice reflect the same characteristics as human AMA. The significant findings of our investigation are as follows: (1) The AMA mouse model manifested the same complication phenotypes of human AMA, including maternal obesity, declining fertility, small for gestational age, and a higher rate of intrauterine fetal death; (2) The AMA mouse model exhibited an increasing systolic blood pressure at late gestation (108.2 ± 7.7 vs. 92.7 ± 5.7 mmHg, P < 0.01) that normalized after delivery similar to human HDP patients; and (3) While HDP and placental dysfunction are complicated, AMA mice and human HDP AMA patients manifested a low serum soluble fms-like tyrosine kinase-1 (sFlt-1) level in late gestation (AMA group vs. control group, mice, 16800.0 ± 10709.5 vs. 26611.9 ± 8702.0 pg/mL, respectively, P < 0.01; human, 8507.6 ± 3298.7 vs. 14816.9 ± 5413.5 pg/mL, respectively, P < 0.05). In conclusion, the aged pregnant mouse model resembled human AMA. The AMA mouse model was complicated with HDP despite the low serum sFlt-1 level. Our findings provide evidence that the serum sFlt-1 level does not necessarily reflect the conventional pathogenesis of HDP in aged human and murine pregnancies and may contribute to the future management of HDP in AMA.
近年来，由于晚婚和辅助生殖技术的进步，西方国家的高龄产妇（AMA）人数有所增加。AMA 的一个主要并发症是妊娠高血压疾病（HDP）。虽然已经有关于人类 AMA 的临床研究报告，但从基础研究中获得的信息有限。在这项研究中，我们使用老年妊娠 ICR 小鼠建立了 AMA 小鼠模型。我们证明，老年妊娠 ICR 小鼠的表型反映了与人类 AMA 相同的特征。我们的研究有以下重要发现：（1）AMA 小鼠模型表现出与人类 AMA 相同的并发症表型，包括母体肥胖、生育力下降、胎儿小于胎龄和宫内胎儿死亡率增加；（2）AMA 小鼠模型在妊娠晚期表现出收缩压升高（108.2±7.7 与 92.7±5.7mmHg，P<0.01），分娩后恢复正常，与人类 HDP 患者相似；（3）虽然 HDP 和胎盘功能障碍很复杂，但 AMA 小鼠和人类 HDP AMA 患者在妊娠晚期表现出低血清可溶性 fms 样酪氨酸激酶-1（sFlt-1）水平（AMA 组与对照组，小鼠分别为 16800.0±10709.5 与 26611.9±8702.0pg/mL，P<0.01；人类分别为 8507.6±3298.7 与 14816.9±5413.5pg/mL，P<0.05）。总之，老年妊娠小鼠模型类似于人类 AMA。尽管血清 sFlt-1 水平较低，但 AMA 小鼠模型仍伴有 HDP。我们的研究结果表明，血清 sFlt-1 水平不一定反映高龄人类和鼠类妊娠中 HDP 的传统发病机制，并可能有助于未来对 AMA 中 HDP 的管理。
