Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF-β1 active form and the consequent enhancement of pSMAD1-5 in males' brain endothelial cells. TGF-β1, in combination with IL-1β, reduces the endothelial expression of CD146 and claudin-5, alters the endothelium–pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex-specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders.

中文翻译：

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母体免疫激活导致男性后代脑血管缺陷和脑出血

脑出血是公认的神经发育障碍的危险因素，是认知功能障碍和精神残疾的早期生物标志物，但导致其发生的途径尚不清楚。我们报告说，免疫刺激剂 Poly I:C 在妊娠第 9 天对怀孕小鼠进行单次子宫内暴露，模拟产前病毒感染和随后的母体免疫激活，诱导脑血管形成缺陷并引起脑出血事件，特别是在男性后代。我们证明母体免疫激活促进了 TGF-β1 活性形式的产生以及随之而来的雄性脑内皮细胞中 pSMAD1-5 的增强。TGF-β1 与 IL-1β 结合，可降低 CD146 和 claudin-5 的内皮表达，改变内皮-周细胞相互作用，导致周细胞覆盖率低，并增加成年后代的出血事件。通过证明在胎儿脑血管生成开始时暴露于 Poly I:C 会导致脑血管发生性别特异性改变，我们为妊娠内感染与神经血管系统异常之间的关联提供了一个机制框架，这可能导致神经精神疾病.