Downregulation of Notch Signaling-Stimulated Genes in Neurovascular Unit Alterations Induced by Chronic Cerebral Hypoperfusion

IF 3.1 4区医学 Q3 IMMUNOLOGY Immunity, Inflammation and Disease Pub Date : 2024-11-28 DOI:10.1002/iid3.70082

Dewen Ru, Zengyu Zhang, Meng Liu, Xuhui Fan, Yuqi Wang, Yufeng Yan, Ersong Wang

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Abstract

Background

Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular cognitive impairment (VCI) and is typically associated with blood–brain barrier (BBB) damage. This study investigates the pathological mechanisms underlying CCH-induced neurovascular unit (NVU) alterations.

Methods

A mouse model of CCH was established using the bilateral common carotid artery stenosis (BCAS) procedure. Decreased cerebral blood flow (CBF) and impaired BBB integrity were assessed. Brain microvessel (BMV)-specific transcriptome profiles were analyzed using RNA-seq, supplemented with published single-cell RNA-seq data.

Results

RNA-seq revealed neuroinflammation-related gene activation and significant downregulation of Notch signaling pathway genes in BMVs post-BCAS. Upregulated differentially expressed genes (DEGs) were enriched in microglia/macrophages, while downregulated DEGs were prominent in endothelial cells and pericytes. Enhanced activation of vascular-associated microglia (VAM) was linked to neurovascular alterations.

Conclusion

CCH induces significant NVU changes, marked by microglia-associated neuroinflammation and Notch signaling downregulation. These insights highlight potential therapeutic targets for treating neuroinflammatory and vascular-related neurodegenerative diseases.

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Notch信号刺激基因在慢性脑灌注不足引起的神经血管单元改变中的下调作用

背景：慢性脑灌注不足（CCH）是造成血管性认知障碍（VCI）的主要原因，通常与血脑屏障（BBB）损伤有关。本研究探讨了CCH诱发神经血管单元（NVU）改变的病理机制：方法：采用双侧颈总动脉狭窄（BCAS）术建立了 CCH 小鼠模型。方法：利用双侧颈总动脉狭窄术（BCAS）建立了 CCH 小鼠模型，评估了脑血流量（CBF）下降和 BBB 完整性受损的情况。使用RNA-seq分析了脑微血管（BMV）特异性转录组图谱，并补充了已发表的单细胞RNA-seq数据：结果：RNA-seq揭示了BCAS后BMV中神经炎症相关基因的激活和Notch信号通路基因的显著下调。小胶质细胞/巨噬细胞中富含上调的差异表达基因（DEGs），而内皮细胞和周细胞中则主要存在下调的差异表达基因。血管相关小胶质细胞（VAM）的活化增强与神经血管的改变有关：结论：CCH 可诱导 NVU 发生重大变化，其特征是与小胶质细胞相关的神经炎症和 Notch 信号下调。这些见解凸显了治疗神经炎症和血管相关神经退行性疾病的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunity, Inflammation and Disease Medicine-Immunology and Allergy

CiteScore

3.60

自引率

0.00%

发文量

146

审稿时长

8 weeks

期刊介绍： Immunity, Inflammation and Disease is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research across the broad field of immunology. Immunity, Inflammation and Disease gives rapid consideration to papers in all areas of clinical and basic research. The journal is indexed in Medline and the Science Citation Index Expanded (part of Web of Science), among others. It welcomes original work that enhances the understanding of immunology in areas including: • cellular and molecular immunology • clinical immunology • allergy • immunochemistry • immunogenetics • immune signalling • immune development • imaging • mathematical modelling • autoimmunity • transplantation immunology • cancer immunology