{"doi":"10.1101/2025.05.02.651303","title":"EBF1 controls an embryonic artery-forming niche that reactivates in pulmonary arterial hypertension","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Developmental programs that orchestrate cell fate and tissue architecture during organogenesis can cause disease when reactivated in adults. Here we identify a population of endothelial cells (ECs) defined by the pioneer factor early B cell factor 1 (EBF1) that controls both pulmonary artery (PA) morphogenesis and pulmonary arterial hypertension (PAH). During embryonic development, the PA emerges from an endothelial niche harbored within the vascular plexus, where\n                  <jats:italic>Aplnr</jats:italic>\n                  <jats:sup>+</jats:sup>\n                  endothelial progenitors give rise to both arterial ECs and EBF1\n                  <jats:italic>\n                    <jats:sup>+</jats:sup>\n                  </jats:italic>\n                  ECs. Rather than directly incorporating into the PA intima, EBF1\n                  <jats:sup>+</jats:sup>\n                  ECs control the branching and maturation of the PA tree through paracrine vasculotrophic signals that direct plexus expansion, arterialization, and mural cell recruitment. Although essential for development, most EBF1\n                  <jats:sup>+</jats:sup>\n                  ECs disappear upon completion of PA morphogenesis. In adult PAH, vascular injury reactivates this developmental program: normally quiescent general capillary ECs re-enter the cell cycle and differentiate into arterial ECs and EBF1\n                  <jats:sup>+</jats:sup>\n                  ECs, reconstituting this artery-forming niche in a maladaptive reprise. Unlike their transient embryonic counterparts, EBF1\n                  <jats:sup>+</jats:sup>\n                  ECs persist within neointimal lesions and express vasculotrophic signals associated with pathological PA remodeling. Capillary-restricted\n                  <jats:italic>Ebf1</jats:italic>\n                  induction combined with endothelial injury recapitulates this program, driving neo-arterialization, neointimal formation, and severe PAH. Conversely, endothelial-targeted AAV-mediated\n                  <jats:italic>Ebf1</jats:italic>\n                  knockdown achieves complete protection in a preclinical model of disease, demonstrating that endothelial EBF1 is necessary for PAH pathogenesis. These findings demonstrate that reactivation and persistence of a transient embryonic artery-forming niche in adulthood can promote pathological vascular remodeling and PAH.\n                </jats:p>","journal":null,"year":null,"id":648739,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1690832,"name":"Timothy Ting-Hsuan Wu","orcid":null,"position":1,"is_corresponding":false},{"id":1188168,"name":"Shenbiao Gu","orcid":null,"position":2,"is_corresponding":false},{"id":630046,"name":"Seunghee Lee","orcid":"0000-0002-3369-0306","position":3,"is_corresponding":false},{"id":1218743,"name":"Hanqiu Zhao","orcid":null,"position":4,"is_corresponding":false},{"id":530618,"name":"Adam Andruska","orcid":"0000-0001-5238-2344","position":5,"is_corresponding":false},{"id":1690837,"name":"Kyle K. Song","orcid":null,"position":6,"is_corresponding":false},{"id":1690838,"name":"Jason L. Chang","orcid":null,"position":7,"is_corresponding":false},{"id":1236543,"name":"Cerianne Huang","orcid":null,"position":8,"is_corresponding":false},{"id":936974,"name":"Ryan Vinh","orcid":"0000-0002-5379-7469","position":9,"is_corresponding":false},{"id":1690840,"name":"Dongeon Kim","orcid":null,"position":10,"is_corresponding":false},{"id":1208865,"name":"Yu Zhu","orcid":"0000-0003-1133-8376","position":11,"is_corresponding":false},{"id":921296,"name":"Evan Bao","orcid":null,"position":12,"is_corresponding":false},{"id":262164,"name":"Stuti Agarwal","orcid":"0000-0002-4436-942X","position":13,"is_corresponding":false},{"id":234889,"name":"Dan Yi","orcid":"0000-0002-2614-5027","position":14,"is_corresponding":false},{"id":1690845,"name":"Aiqing Cao","orcid":null,"position":15,"is_corresponding":false},{"id":256143,"name":"Junliang Pan","orcid":"0000-0002-2373-0917","position":16,"is_corresponding":false},{"id":1187764,"name":"Peter N. 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Nicolls","orcid":"0000-0001-9473-7422","position":29,"is_corresponding":false},{"id":292030,"name":"Wen Tian","orcid":"0000-0002-0569-318X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"EBF1 controls an embryonic artery-forming niche that reactivates in pulmonary arterial hypertension","abstract":"Developmental programs that orchestrate cell fate and tissue architecture during organogenesis can cause disease when reactivated in adults. Here we identify a population of endothelial cells (ECs) defined by the pioneer factor early B cell factor 1 (EBF1) that controls both pulmonary artery (PA) morphogenesis and pulmonary arterial hypertension (PAH). During embryonic development, the PA emerges from an endothelial niche harbored within the vascular plexus, where  Aplnr + endothelial progenitors give rise to both arterial ECs and EBF1  + ECs. Rather than directly incorporating into the PA intima, EBF1  + ECs control the branching and maturation of the PA tree through paracrine vasculotrophic signals that direct plexus expansion, arterialization, and mural cell recruitment. Although essential for development, most EBF1  + ECs disappear upon completion of PA morphogenesis. In adult PAH, vascular injury reactivates this developmental program: normally quiescent general capillary ECs re-enter the cell cycle and differentiate into arterial ECs and EBF1  + ECs, reconstituting this artery-forming niche in a maladaptive reprise. Unlike their transient embryonic counterparts, EBF1  + ECs persist within neointimal lesions and express vasculotrophic signals associated with pathological PA remodeling. Capillary-restricted  Ebf1 induction combined with endothelial injury recapitulates this program, driving neo-arterialization, neointimal formation, and severe PAH. Conversely, endothelial-targeted AAV-mediated  Ebf1 knockdown achieves complete protection in a preclinical model of disease, demonstrating that endothelial EBF1 is necessary for PAH pathogenesis. These findings demonstrate that reactivation and persistence of a transient embryonic artery-forming niche in adulthood can promote pathological vascular remodeling and PAH.","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"Palo Alto Veterans Institute for Research","grant_id":"HL158714","title":null},{"funder_name":"VA Palo Alto Health Care System","grant_id":"I01 BX005628","title":null},{"funder_name":"Palo Alto Veterans Institute for Research","grant_id":"HL138473","title":null},{"funder_name":"Palo Alto Veterans Institute for Research","grant_id":"HL150583","title":null}],"total_grants":4,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/05/07/2025.05.02.651303.full.pdf","host_type":"repository"}],"fields_of_study":[],"mesh_terms":[],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T02:55:26.241071Z","pmid":null,"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":[]}