Minato Takahiro, Ito Takuya, Kasahara Yoshiyuki, Ooshio Sayaka, Fushima Tomofumi, Sekimoto Akiyo, Takahashi Nobuyuki, Yaegashi Nobuo, Kimura Yoshitaka
Advanced Interdisciplinary Biomedical Engineering, Tohoku University Graduate School of Medicine, Sendai, Japan.
Center for Development of Advanced Medical Technology, Jichi Medical University, Shimotsuke, Japan.
Front Physiol. 2018 May 18;9:478. doi: 10.3389/fphys.2018.00478. eCollection 2018.
Fetal growth restriction (FGR) is a risk factor exacerbating a poor neurological prognosis at birth. A disease exacerbating a poor neurological prognosis is cerebral palsy. One of the cause of this disease is cerebral hemorrhage including intraventricular hemorrhage. It is believed to be caused by an inability to autoregulate cerebral blood flow as well as immaturity of cerebral vessels. Therefore, if we can evaluate the function of autonomic nerve, cerebral hemorrhage risk can be predicted beforehand and appropriate delivery management may be possible. Here dysfunction of autonomic nerve in mouse FGR fetuses was evaluated and the relationship with cerebral hemorrhage incidence when applying hypoxic load to resemble the brain condition at the time of delivery was examined. Furthermore, FGR incidence on cerebral nerve development and differentiation was examined at the gene expression level. FGR model fetuses were prepared by ligating uterine arteries to reduce placental blood flow. To compare autonomic nerve function in FGR mice with that in control mice, fetal short term variability (STV) was measured from electrocardiograms. In the FGR group, a significant decrease in the STV was observed and dysfunction of cardiac autonomic control was confirmed. Among genes related to nerve development and differentiation, and , which are necessary for neural differentiation and plasticity, were expressed at reduced levels in FGR fetuses. Under normal conditions, and are expressed mid-embryogenesis and are related to neural differentiation, but they are not expressed during late embryonic development. The expression of these two genes increased in FGR fetuses, suggesting that neural differentiation is delayed with FGR. Uterine and ovarian arteries were clipped and periodically opened to give a hypoxic load mimicking the time of labor, and the bleeding rate significantly increased in the FGR group. This suggests that FGR deteriorates cardiac autonomic control, which becomes a risk factor for cerebral hemorrhage onset at birth. This study demonstrated that cerebral hemorrhage risk may be evaluated before parturition for FGR management by evaluating the STV. Further, this study suggests that choosing an appropriate delivery timing and delivery method contributes to neurological prognosis improvement.
胎儿生长受限（FGR）是加剧出生时神经预后不良的一个风险因素。加剧神经预后不良的一种疾病是脑瘫。这种疾病的病因之一是脑出血，包括脑室内出血。据信这是由于无法自动调节脑血流以及脑血管不成熟所致。因此，如果我们能够评估自主神经功能，就可以预先预测脑出血风险，并可能进行适当的分娩管理。在此，对小鼠FGR胎儿的自主神经功能障碍进行了评估，并研究了在施加低氧负荷以模拟分娩时脑状况时与脑出血发生率的关系。此外，在基因表达水平上研究了FGR对脑神经发育和分化的影响。通过结扎子宫动脉以减少胎盘血流来制备FGR模型胎儿。为了比较FGR小鼠和对照小鼠的自主神经功能，从心电图测量胎儿短期变异性（STV）。在FGR组中，观察到STV显著降低，并证实了心脏自主控制功能障碍。在与神经发育和分化相关的基因中，神经分化和可塑性所必需的[具体基因1]和[具体基因2]在FGR胎儿中的表达水平降低。在正常情况下，[具体基因1]和[具体基因2]在胚胎中期表达并与神经分化相关，但在胚胎后期发育期间不表达。这两个基因在FGR胎儿中的表达增加，表明FGR导致神经分化延迟。夹闭子宫和卵巢动脉并定期开放以施加模拟分娩时的低氧负荷，FGR组的出血率显著增加。这表明FGR会使心脏自主控制功能恶化，这成为出生时脑出血发作的一个风险因素。这项研究表明，通过评估STV可以在分娩前评估FGR管理的脑出血风险。此外，这项研究表明选择合适的分娩时机和分娩方式有助于改善神经预后。
