{"doi":"10.1016/j.jcmgh.2023.06.005","title":"Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of Cholangitis","abstract":"Background & Aims Primary sclerosing cholangitis (PSC) leads to ductular reaction and fibrosis and is complicated by vascular dysfunction. Cholangiocyte and endothelial cell crosstalk modulates their proliferation in cholestatic models. Endothelin (ET)-1 and ET-2 bind to their receptor, ET-A, and cholangiocytes are a key source of ET-1 after bile duct ligation. We aimed to evaluate the therapeutic potential of ET-A inhibition in PSC and biliary-endothelial crosstalk mediated by this pathway. Methods Wild-type and multidrug resistance 2 knockout ( Mdr2 -/ - ) mice at 12 weeks of age were treated with vehicle or Ambrisentan (ET-A antagonist) for 1 week by daily intraperitoneal injections. Human control and PSC samples were used. Results Mdr2 -/- mice at 4, 8, and 12 weeks displayed angiogenesis that peaked at 12 weeks. Mdr2 -/- mice at 12 weeks had enhanced biliary ET-1/ET-2/ET-A expression and secretion, whereas human PSC had enhanced ET-1/ET-A expression and secretion. Ambrisentan reduced biliary damage, immune cell infiltration, and fibrosis in Mdr2 -/- mice. Mdr2 -/- mice had squamous cholangiocytes with blunted microvilli and dilated arterioles lacking cilia; however, Ambrisentan reversed these alterations. Ambrisentan decreased cholangiocyte expression of pro-angiogenic factors, specifically midkine, through the regulation of cFOS. In vitro , ET-1/ET-A caused cholangiocyte senescence, endothelial cell angiogenesis, and macrophage inflammation. In vitro , human PSC cholangiocyte supernatants increased endothelial cell migration, which was blocked with Ambrisentan treatment. Conclusions ET-A inhibition reduced biliary and liver damage in Mdr2 -/- mice. ET-A promotes biliary angiocrine signaling that may, in turn, enhance angiogenesis. Targeting ET-A may prove therapeutic for PSC, specifically patients displaying vascular dysfunction.","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2023,"id":328003,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"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":70025,"name":"Guido Carpino","orcid":"0000-0001-8570-2519","position":1,"is_corresponding":false},{"id":257778,"name":"Lixian Chen","orcid":"0000-0001-9413-4592","position":2,"is_corresponding":false},{"id":314389,"name":"Debjyoti Kundu","orcid":"0000-0002-7209-0100","position":3,"is_corresponding":false},{"id":1049334,"name":"Payton G. Wills","orcid":null,"position":4,"is_corresponding":false},{"id":257774,"name":"Burcin Ekser","orcid":"0000-0003-0741-8007","position":5,"is_corresponding":false},{"id":279142,"name":"Paolo Onori","orcid":"0000-0002-7195-3760","position":6,"is_corresponding":false},{"id":279143,"name":"Eugenio Gaudio","orcid":"0000-0001-6180-3091","position":7,"is_corresponding":false},{"id":257786,"name":"Gianfranco Alpini","orcid":"0000-0002-6658-3021","position":8,"is_corresponding":false},{"id":257785,"name":"Heather Francis","orcid":"0000-0002-3466-3545","position":9,"is_corresponding":false},{"id":257783,"name":"Lindsey Kennedy","orcid":"0000-0001-9224-8940","position":10,"is_corresponding":false},{"id":867074,"name":"Travis Owen","orcid":"0009-0006-7989-962X","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:08:47.581262Z","pmid":"37336290","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":[]}