Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.
IRCCS Humanitas Clinical and Research Center, Rozzano, Italy.
EMBO J. 2022 Dec 1;41(23):e111192. doi: 10.15252/embj.2022111192. Epub 2022 Oct 31.
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.
脑内出血被认为是神经发育障碍的风险因素，也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未明确。我们报告称，在妊娠第 9 天对怀孕小鼠进行单次宫内暴露于免疫刺激剂 Poly I:C，可模拟产前病毒感染和随之发生的母体免疫激活，导致脑血管形成缺陷，并导致脑内出血事件，特别是在雄性后代中。我们证明，母体免疫激活促进 TGF-β1 活性形式的产生，并随后增强雄性大脑血管内皮细胞中的 pSMAD1-5。TGF-β1 与 IL-1β 结合，降低内皮细胞 CD146 和 Claudin-5 的表达，改变内皮细胞-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。通过表明在胎儿大脑血管生成开始时暴露于 Poly I:C 会导致雄性大脑血管的性别特异性改变，我们为宫内感染与神经血管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障碍。
