{"doi":"10.1101/2023.04.03.535167","title":"Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway","abstract":"Abstract Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-NO-CCL2 axis as a pivotal mechanism controlling BBB integrity and repair, while providing insights for a novel therapeutic approach against BBB-related CNS disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391739,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254711,"name":"Ju-Yeon Jo","orcid":"0000-0001-8939-1623","position":1,"is_corresponding":false},{"id":552582,"name":"Chih‐Yen Wang","orcid":"0009-0008-8270-6491","position":2,"is_corresponding":false},{"id":1164936,"name":"Heavin Oh","orcid":null,"position":3,"is_corresponding":false},{"id":333842,"name":"Tiffany J. Choy","orcid":"0000-0001-6501-2123","position":4,"is_corresponding":false},{"id":1164937,"name":"Kyoung-In Kim","orcid":null,"position":5,"is_corresponding":false},{"id":28360,"name":"Angelo D’Alessandro","orcid":"0000-0002-2258-6490","position":6,"is_corresponding":false},{"id":257300,"name":"Yana K. Reshetnyak","orcid":null,"position":7,"is_corresponding":false},{"id":259925,"name":"Sung Yun Jung","orcid":"0000-0003-1521-7977","position":8,"is_corresponding":false},{"id":458445,"name":"Zheng Chen","orcid":"0000-0002-2464-5474","position":9,"is_corresponding":false},{"id":480875,"name":"Sean P. Marrelli","orcid":"0000-0001-8476-4785","position":10,"is_corresponding":false},{"id":254730,"name":"Hyun Kyoung Lee","orcid":"0000-0001-5793-4398","position":11,"is_corresponding":false},{"id":1023976,"name":"Qi Ye","orcid":"0000-0001-7352-548X","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T01:18:47.408273Z","pmid":"37066295","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}