{"doi":"10.1101/2025.08.20.671398","title":"Modulation of miR-23b Wnt/β-catenin Axis Strengthens Endothelial Barrier Properties","abstract":"Blood-brain barrier (BBB) disruption drives stroke and other CNS disorders pathology, yet restoring its integrity remains challenging. Using an unbiased anti-miR lentiviral screen, miR-23b was identified as a critical negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b using anti-miR-23b, validated by Wnt-reporter, Wnt-rescue, and eCLIP analysis, demonstrates that BEC miR-23b silencing in BECs, enhances junctional protein expression and strengthens barrier function while suppressing transcellular transport. Global multi-omics analysis reveals that miR-23b acts as a robust driver of angiogenesis-specific genes and proteins. Conversely, anti-miR-23b induces the expression of factors essential for BBB stabilization and repair. Notably, anti-miR-23b enhances these protective barrier properties through the multi-faceted regulation of Wnt/β-catenin, TGF-β, Notch, and VEGF signaling mechanisms. Using a 3D microfluidic platform, anti-miR-23b was shown to foster BBB repair by accelerating vessel maturation and enhancing resilience against ischemic injury. Proof-of-concept studies show that BEC specific AAVBR1-anti-miR-23b gene therapy reinforces BBB tight junctions, reduces BBB leakage, and improves outcome measures in a transient middle cerebral artery occlusion (t-MCAO) stroke model. Thus, miR-23b is a critical regulator of cerebrovascular integrity, positioning anti-miR-23b as a promising RNA-based therapy to enhance BBB stability and repair in stroke and other CNS disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":573268,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1480061,"name":"Rose Presby","orcid":"0000-0002-6506-2822","position":1,"is_corresponding":false},{"id":1480062,"name":"Sara Nakanishi","orcid":"0009-0009-3332-3993","position":2,"is_corresponding":false},{"id":1480484,"name":"Iben Daugaard Krog","orcid":null,"position":3,"is_corresponding":false},{"id":1480063,"name":"Douglas Jury","orcid":"0000-0001-9731-4855","position":4,"is_corresponding":false},{"id":1068042,"name":"Brian R. Lawson","orcid":null,"position":5,"is_corresponding":false},{"id":272299,"name":"Dritan Agalliu","orcid":"0000-0002-1365-6450","position":7,"is_corresponding":false},{"id":1480064,"name":"Irene Munk Pedersen","orcid":"0000-0003-4267-7370","position":8,"is_corresponding":false},{"id":1166597,"name":"Danny Jamoul","orcid":null,"position":9,"is_corresponding":false},{"id":631031,"name":"Jakob Körbelin","orcid":"0000-0002-5435-7182","position":12,"is_corresponding":false},{"id":159417,"name":"Lewis M. Brown","orcid":null,"position":13,"is_corresponding":false},{"id":7417,"name":"Vilas Menon","orcid":"0000-0002-4096-8601","position":14,"is_corresponding":false},{"id":1480060,"name":"Victor H. Martinez","orcid":"0000-0002-9243-9568","position":0,"is_corresponding":true}],"reference_count":98,"raw_metadata":null,"created_at":"2026-07-19T02:57:32.445190Z","pmid":"42244683","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":[]}