Figueroa Esteban G, Paz Adolfo A, Jiménez Tamara A, Meza-Vilches Osvaldo, Palma C Daniel, Muños-Guzman Fernanda, Beñaldo Felipe, Herrera Emilio A, González-Candia Alejandro
Laboratory of Fetal Neuroprogramming, Institute of Health Sciences, University of O'Higgins, Rancagua, Chile.
Laboratory of Vascular Function & Reactivity, Pathophysiology Program, ICBM, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Pediatr Res. 2025 Sep 9. doi: 10.1038/s41390-025-04345-x.
Fetal growth restriction (FGR) causes an adaptive redistribution of the cardiac output towards sustained cerebral vasodilation. However, the consequences of FGR and cerebral vasodilatation due to fetal hypoxia on the blood-brain barrier (BBB) are still poorly studied. This study assesses BBB permeability in the neonatal cortex of pups gestated under intrauterine hypobaric hypoxia.
15 Guinea pig (Cavia porcellus) newborns were used in this study; 8 were gestated in normoxia (Nx), and 7 were gestated under chronic hypobaric hypoxia (Hx). Fetal examinations by ultrasound were assessed. At birth, pups were euthanized, and the cerebral cortex was collected to determine gene and protein expression. The permeability was quantified by immunolocalization of perivascular albumin in the prefrontal cortex BBB.
The brain-sparing phenotype was associated with increased medial cerebral artery vasodilation during gestation and carotid endothelial vasodilation at birth. Additionally, gestational hypoxia decreased the protein levels of claudin-5 and claudin-12 in the neonatal cortex. Finally, albumin-immunopositive areas significantly increased in the brain parenchyma in the Hx neonatal cortex.
Our findings demonstrate that gestational hypoxia is associated with changes in the expression of genes and proteins related to the paracellular permeability of the BBB, which appears relevant to normal neurodevelopmental processes in perinatal life.
Gestational hypoxia generated a redistribution of flow (brain-sparing effects) associated with an increase in the cerebroplacental index and a growth restriction at birth using guinea pigs as an FGR model. The brain-sparing phenotype is associated with a decrease in the expression of claudins in the cerebral vasculature and increased BBB permeability in newborns gestated in hypobaric hypoxia. The observed permeability of the BBB in the neonatal cortex resembles the permeability phenotypes of postnatal hypoxia models, such as those of cerebral infarction or neonatal ischemic encephalopathy.
胎儿生长受限（FGR）会导致心输出量适应性重新分配，以维持脑循环血管舒张。然而，FGR及胎儿缺氧导致的脑血管舒张对血脑屏障（BBB）的影响仍研究不足。本研究评估宫内低压缺氧妊娠的幼崽新生皮质中的BBB通透性。
本研究使用15只豚鼠（豚鼠属）新生幼崽；8只在常氧（Nx）环境下妊娠，7只在慢性低压缺氧（Hx）环境下妊娠。通过超声评估胎儿情况。出生时，将幼崽安乐死，收集大脑皮质以测定基因和蛋白质表达。通过前额叶皮质BBB中血管周围白蛋白的免疫定位来量化通透性。
脑保护表型与妊娠期间大脑中动脉舒张增加及出生时颈动脉内皮舒张有关。此外，妊娠缺氧降低了新生皮质中claudin-5和claudin-12的蛋白质水平。最后，Hx新生皮质脑实质中白蛋白免疫阳性区域显著增加。
我们的研究结果表明，妊娠缺氧与BBB细胞旁通透性相关基因和蛋白质表达的变化有关，这似乎与围产期正常神经发育过程相关。
以豚鼠作为FGR模型，妊娠缺氧导致血流重新分配（脑保护作用），伴有脑胎盘指数增加及出生时生长受限。脑保护表型与脑血管中claudin表达降低及低压缺氧妊娠新生幼崽BBB通透性增加有关。在新生皮质中观察到的BBB通透性类似于产后缺氧模型（如脑梗死或新生儿缺血性脑病模型）的通透性表型。
