Maternal immune activation leads to defective brain blood vessels and intracerebral hemorrhages in male offspring

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 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.

脑内出血（Intracerebral Hemorrhages）是公认的神经发育障碍风险因素，同时也是认知功能障碍与精神残疾的早期生物标志物，但目前其发生的相关通路尚未被完全阐明。本研究证实，在妊娠第9天向妊娠小鼠宫内单次给予免疫刺激剂Poly I:C（Poly I:C）以模拟产前病毒感染及随之而来的母体免疫激活，可诱导脑血管形成异常，并仅在雄性后代中引发脑内出血事件。我们进一步发现，母体免疫激活会促进转化生长因子-β1（TGF-β1）活性形式的产生，进而增强雄性小鼠脑内皮细胞中pSMAD1-5的表达水平。转化生长因子-β1联合白细胞介素-1β（IL-1β）可降低内皮细胞CD146与紧密连接蛋白-5（Claudin-5）的表达，改变内皮细胞-周细胞的相互作用，导致周细胞覆盖率降低，并增加成年后代的脑内出血事件发生率。本研究通过揭示在胎儿脑血管生成初期暴露于Poly I:C会引发性别特异性的脑血管异常，为妊娠期间感染与神经血管异常之间的关联提供了机制层面的解释框架，该关联可能参与神经精神疾病的发生发展。