Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of CholangitisSummary

Travis Owen; Guido Carpino; Lixian Chen; Debjyoti Kundu; Payton Wills; Burcin Ekser; Paolo Onori; Eugenio Gaudio; Gianfranco Alpini; Heather Francis; Lindsey Kennedy

Cellular and Molecular Gastroenterology and Hepatology (Jan 2023)

Endothelin Receptor-A Inhibition Decreases Ductular Reaction, Liver Fibrosis, and Angiogenesis in a Model of CholangitisSummary

Travis Owen,
Guido Carpino,
Lixian Chen,
Debjyoti Kundu,
Payton Wills,
Burcin Ekser,
Paolo Onori,
Eugenio Gaudio,
Gianfranco Alpini,
Heather Francis,
Lindsey Kennedy

Affiliations

Travis Owen: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Guido Carpino: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
Lixian Chen: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Debjyoti Kundu: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Payton Wills: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
Burcin Ekser: Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Paolo Onori: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
Eugenio Gaudio: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
Gianfranco Alpini: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
Heather Francis: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
Lindsey Kennedy: Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Correspondence Address correspondence to: Lindsey Kennedy, PhD, Department of Medicine, Indiana University School of Medicine, Department of Research, Richard L. Roudebush VA Medical Center, 702 Rotary Circle, Room 007, Indianapolis, Indiana 46202.

Journal volume & issue: Vol. 16, no. 4
pp. 513 – 540

Abstract

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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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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