{"doi":"10.1084/jem.20211390","title":"Endothelial <i>Rbpj</i> deletion normalizes Notch4-induced brain arteriovenous malformation in mice","abstract":"Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression of constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% of mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, a mediator of Notch signaling, in endothelium from P16, by combining tet-repressible Notch4*tetEC with tamoxifen-inducible Rbpj deletion. Established pathologies, including AV connection diameter, AV shunting, vessel tortuosity, intracerebral hemorrhage, tissue hypoxia, life expectancy, and arterial marker expression were improved, compared with Notch4*tetEC mice without Rbpj deletion. Similarly, Rbpj deletion from P21 induced advanced bAVM regression. After complete AVM normalization induced by repression of Notch4*tetEC, virtually no bAVM relapsed, despite Notch4*tetEC re-expression in adults. Thus, inhibition of endothelial Rbpj halted Notch4*tetEC bAVM progression, normalized bAVM abnormalities, and restored microcirculation, providing proof of concept for targeting a downstream mediator to treat AVM pathologies despite a sustained causal molecular lesion.","journal":"The Journal of Experimental Medicine","year":2022,"id":260440,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":914136,"name":"Xuetao Zhang","orcid":"0000-0003-2930-1176","position":1,"is_corresponding":false},{"id":839948,"name":"Kunal P. Raygor","orcid":"0000-0002-5517-7706","position":2,"is_corresponding":false},{"id":304955,"name":"Shaoxun Wang","orcid":"0000-0002-1439-021X","position":3,"is_corresponding":false},{"id":267675,"name":"Andrew W. Bollen","orcid":"0000-0001-9852-5224","position":4,"is_corresponding":false},{"id":914137,"name":"Rong A. Wang","orcid":"0000-0001-7882-2475","position":5,"is_corresponding":false},{"id":657188,"name":"Corinne M. Nielsen","orcid":"0000-0002-8500-6035","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T00:26:07.666421Z","pmid":"36441145","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":[]}