Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven, Herestraat 49, Box 805, 3000, Leuven, Belgium.
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.
Sci Rep. 2022 Nov 16;12(1):19720. doi: 10.1038/s41598-022-22895-6.
Fetal growth restriction is one of the leading causes of perinatal mortality and morbidity and has consequences that extend well beyond the neonatal period. Current management relies on timely delivery rather than improving placental function. Several prenatal strategies have failed to show benefit in clinical trials after promising results in animal models. Most of these animal models have important developmental and structural differences compared to the human and/or are insufficiently characterized. We aimed to describe placental function and structure in an FGR rabbit model, and to characterize the early brain and lung developmental morbidity using a multimodal approach. FGR was induced in time-mated rabbits at gestational day 25 by partial uteroplacental vessel ligation in one horn. Umbilical artery Doppler was measured before caesarean delivery at gestational day 30, and placentas were harvested for computed microtomography and histology. Neonates underwent neurobehavioral or pulmonary functional assessment the day after delivery, followed by brain or lung harvesting, respectively. Neuropathological assessment included multiregional quantification of neuron density, apoptosis, astrogliosis, cellular proliferation, and oligodendrocyte progenitors. Brain region volumes and diffusion metrics were obtained from ex-vivo brain magnetic resonance imaging. Lung assessment included biomechanical tests and pulmonary histology. Fetal growth restriction was associated with labyrinth alterations in the placenta, driven by fetal capillary reduction, and overall reduced vessels volume. FGR caused altered neurobehavior paralleled by regional neuropathological deficits and reduced fractional anisotropy in the cortex, white matter, and hippocampus. In addition, FGR kittens presented functional alterations in the peripheral lung and structurally underdeveloped alveoli. In conclusion, in a uteroplacental insufficiency FGR rabbit model, placental vascular alterations coincide with neurodevelopmental and pulmonary disruption.
胎儿生长受限是围产儿死亡和发病的主要原因之一，其后果远远超出新生儿期。目前的治疗方法依赖于及时分娩，而不是改善胎盘功能。一些产前策略在动物模型中取得了有希望的结果后，在临床试验中未能显示出益处。与人类相比，这些动物模型中的大多数在发育和结构上存在重要差异，或者特征描述不足。我们旨在描述 FGR 兔模型中的胎盘功能和结构，并采用多模态方法描述早期脑和肺发育不良。在妊娠第 25 天，通过在一个角上结扎部分子宫胎盘血管，在时间匹配的兔子中诱导胎儿生长受限。在妊娠第 30 天行剖宫产前测量脐动脉多普勒，并采集胎盘进行计算微断层扫描和组织学检查。新生儿在分娩后第二天进行神经行为或肺功能评估，然后分别进行大脑或肺组织采集。神经病理学评估包括神经元密度、细胞凋亡、星形胶质增生、细胞增殖和少突胶质前体细胞的多区域定量。从离体脑磁共振成像中获得脑区体积和扩散指标。肺评估包括生物力学测试和肺组织学检查。胎儿生长受限与胎盘内迷路改变有关，这是由胎儿毛细血管减少和整体血管体积减少引起的。FGR 导致神经行为改变，伴有区域性神经病理学缺陷和皮质、白质和海马体的各向异性分数降低。此外，FGR 小猫的外周肺功能发生改变，肺泡结构发育不全。总之，在胎盘功能不全的 FGR 兔模型中，胎盘血管改变与神经发育和肺功能障碍同时发生。
