Li Shan-Shan, Guo Miao, Long Yao, Cai Yuang, Zhao Ying, Huang Shaoyuan, Yang Houzhi, Fan Yonggang, Chen Xu, Jin Xin
School of Medicine, Nankai University, Tianjin, China.
Tianjin Medical University, Tianjin, China.
Clin Transl Med. 2025 Mar;15(3):e70260. doi: 10.1002/ctm2.70260.
Maternal immune activation (MIA) is recognised as a risk factor in the neurodevelopmental disorders. However, the precise molecular pathways through which MIA disrupts neurovascular function remain largely unexplored. Here, we identify a novel MIA-associated brain endothelial piRNA (MIABEPIR) involved in regulating BMEC function and BBB integrity. RNA microarray analysis of foetal brain tissue from MIA-exposed mice revealed significant changes in piRNA expression, including a marked upregulation of MIABEPIR upregulated piRNAs. Immunofluorescence and FISH confirmed that MIABEPIR is localised in the microvascular endothelial cells of the brain. MIABEPIR overexpression enhances BMEC proliferation and angiogenesis but disrupts BBB integrity. In vivo, intracranial administration of lentiviral MIABEPIR in foetal mice resulted in marked BBB disruption. Mechanistically, we identified DAPK2 as a downstream target of MIABEPIR, leading to its downregulation. This suppression of DAPK2 inhibits autophagy in BMECs, suggesting that MIABEPIR modulates endothelial cell autophagy through the DAPK2 pathway. Our findings reveal a novel piRNA-mediated regulatory mechanism in neurovascular function during MIA and highlight MIABEPIR's role in MIA-induced neurodevelopmental abnormalities. Targeting the MIABEPIR-DAPK2 axis represents a potential therapeutic strategy for addressing neurovascular dysfunction in neurodevelopmental disorders associated with maternal immune stress.
母体免疫激活（MIA）被认为是神经发育障碍的一个风险因素。然而，MIA破坏神经血管功能的确切分子途径在很大程度上仍未被探索。在这里，我们鉴定出一种新的与MIA相关的脑内皮piRNA（MIABEPIR），它参与调节脑微血管内皮细胞（BMEC）功能和血脑屏障（BBB）完整性。对暴露于MIA的小鼠胎儿脑组织进行RNA微阵列分析，发现piRNA表达有显著变化，包括MIABEPIR上调的piRNA明显上调。免疫荧光和荧光原位杂交证实MIABEPIR定位于脑微血管内皮细胞中。MIABEPIR过表达增强BMEC增殖和血管生成，但破坏BBB完整性。在体内，向胎儿小鼠颅内注射慢病毒MIABEPIR导致明显的BBB破坏。从机制上讲，我们鉴定出DAPK2是MIABEPIR的下游靶点，导致其下调。DAPK2的这种抑制作用抑制了BMEC中的自噬，表明MIABEPIR通过DAPK2途径调节内皮细胞自噬。我们的研究结果揭示了MIA期间神经血管功能中一种新的piRNA介导的调节机制，并突出了MIABEPIR在MIA诱导的神经发育异常中的作用。靶向MIABEPIR-DAPK2轴代表了一种潜在的治疗策略，用于解决与母体免疫应激相关的神经发育障碍中的神经血管功能障碍。
