{"doi":"10.1172/jci.insight.164862","title":"Redistribution of the chromatin remodeler Brg1 directs smooth muscle–derived adventitial progenitor–to–myofibroblast differentiation and vascular fibrosis","abstract":"Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-β1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-β1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-β1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits.","journal":"JCI Insight","year":2023,"id":336093,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.945,"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":324289,"name":"Sizhao Lu","orcid":"0000-0002-9892-8784","position":1,"is_corresponding":false},{"id":324292,"name":"Allison Dubner","orcid":"0000-0001-8027-7410","position":2,"is_corresponding":false},{"id":324291,"name":"Keith A. Strand","orcid":"0000-0001-8885-0162","position":3,"is_corresponding":false},{"id":324293,"name":"Marie F Mutryn","orcid":"0000-0003-2166-6904","position":4,"is_corresponding":false},{"id":1066492,"name":"Aaron Pilotti-Riley","orcid":"0000-0002-3670-024X","position":5,"is_corresponding":false},{"id":310928,"name":"Etienne Danis","orcid":"0000-0002-5651-8111","position":6,"is_corresponding":false},{"id":32253,"name":"Raphael A. Nemenoff","orcid":"0000-0002-9051-814X","position":7,"is_corresponding":false},{"id":324294,"name":"Karen S. Moulton","orcid":"0000-0001-9836-6614","position":8,"is_corresponding":false},{"id":324295,"name":"Mark W. Majesky","orcid":"0000-0003-4267-6220","position":9,"is_corresponding":false},{"id":324296,"name":"Mary C.M. Weiser‐Evans","orcid":"0000-0002-6239-2412","position":10,"is_corresponding":false},{"id":324290,"name":"Austin Jolly","orcid":"0000-0001-6458-4648","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:10:17.243221Z","pmid":"36976650","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":[]}