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Rutin ameliorates stress-induced blood‒brain barrier dysfunction and cognitive decline via the endothelial HDAC1‒Claudin-5 axis

ABSTRACT: Background: Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive. Methods: In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB. Results: We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation. Conclusions: This work establishes a protective role of rutin in regulating BMEC function and BBB integrity and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288810 | GEO | 2025/04/09

REPOSITORIES: GEO

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Project description:Next-generation sequencing (NGS) has significantly facilitated the analysis of the gene profile and elucidated the molecular mechanisms important for specific cell lineage differentiated from human pluripotent stem cells (hPSCs). Here we report the application of RNA-sequencing technology for transcriptome profile of primary human brain microvascular endothelial cells (BMECs) and hPSC-derived BMECs, and comparison of transcriptomes among cells, including hPSCs, mesodermal progenitors, ectodermal progenitors, endodermal progenitors, hBMECs and hPSC-derived BMECs from hPSCs. Four different BMEC samples differentiated from hPSCs by two different methods and hBMECs were performed in IIIumina HiSeq2500. The resulting sequence reads (about 20 million reads per sample) were mapped to human genome (hg19) using HISAT, and the RefSeq transcript levels (FPKMs) were quantified using the python script rpkmforgenes.py. We next analyzed the expression of a subset of genes that regulate key BBB attributes, including tight junctions and molecular transporters. The gene set comprises 20 tight junction-related genes and an unbiased list of all 25 CLDN genes, all 407 solute carrier (SLC) transporters, and all 53 ATP-binding cassette (ABC) transporters regardless of prior knowledge of BBB association. Primary human BMECs expressed 234 of these genes. BMECs differentiated from hPSCs via the defined method expressed many of these same genes (206 of 234 (88%)) as did BMECs differentiated via the UM method (208 of 234 (89%), indicating a close similarity between hPSC-derived BMECs and primary human BMECs with respect to transcripts having likely relevance to BBB function. RNA sequencing was used to compare global gene expression profiles in the hPSC-derived BMECs with BMECs generated from our previously reported co-differentiation system and primary human BMECs. As expected, hPSC-derived BMECs from three independent differentiations clustered closely and were similar to those generated from the undefined UM platform. Moreover, the hPSC-derived BMECs clustered with primary human BMECs and were distinct from undifferentiated hPSCs and hPSC-derived ectoderm, endoderm and mesodermThis study provides detailed transcriptome comparison between hBMECs and hPSC-derived BMECs and unveils important genes related BMEC phenotypes.

Project description:The low permeability and high selectivity of the blood vessels of the brain and central nervous system (CNS) characterize the blood-brain barrier (BBB). Tight junctions, a lack of fenestrations, and low rates of transcytosis in the endothelial cells of the vasculature prevent passive diffusion of most molecules other than water, gases and some lipid soluble molecules (Obermeier, Daneman, & Ransohoff, 2013). Any additional nutrients must be transported across the barrier with the help of transporter proteins. Two protein families account for most transporters. ABC transporters use ATP to power primary-active transport to move molecules across the BBB against an electrochemical gradient, frequently excluding drugs from entering the brain. Some SLC transporters facilitate transport of solutes along an electrochemical gradient, while others permit secondary-active transport by coupling the flow of a solute traveling down the electrochemical gradient to power another solute against its electrochemical gradient. Brain microvessel endothelial cells (BMEC) from human cerebral cortex were enriched through a homogenization and centrifugation procedure. Two BMEC and two tissue were sequenced with paired-end reads on a SOLiD 5500 Wildfire. Raw data was aligned using LifeScope Genomic Analysis, gene expression determined through Cufflinks, and splice junctions identified by aligning to a custom database of known to known and known to novel junctions. We found numerous examples of transporters with enriched expression in the isolated BMECs compared to whole brain tissue. In total, 131 transporter genes or pseudogenes (109 SLC, 22 ABC) are enriched at least 1.25 fold in BMEC enriched samples, and 57 of these are enriched over 2-fold (50 SLC, 7 ABC). Thirteen genes were found to have at least twice as many counts in BMEC enriched samples than in whole tissue for at least one alternative splice junction. Inversely, 23 genes were found to have at least one alternative splice junction with half as many counts in BMEC enriched samples than in whole tissue.

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Rutin ameliorates stress-induced blood‒brain barrier dysfunction and cognitive decline via the endothelial HDAC1‒Claudin-5 axis

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