title: Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1.
abstract: Endothelin-1 (ET-1) is a 21-amino acid peptide with various biological activities including vasoconstriction and cell proliferation. To clarify the physiological and pathophysiological role of ET-1, we disrupted the mouse Edn1 locus encoding ET-1 by gene targeting and demonstrated that ET-1 is essential to the normal development of pharyngeal arch-derived tissues and organs. In this study, we focused on the phenotypic manifestations of Edn1-/- homozygous mice in the cardiovascular system. Edn1-/- homozygotes display cardiovascular malformations including interrupted aortic arch (2.3%), tubular hypoplasia of the aortic arch (4.6%), aberrant right subclavian artery (12.9%), and ventricular septal defect with abnormalities of the outflow tract (48.4%). The frequency and extent of these abnormalities are increased by treatment with neutralizing monoclonal antibodies or a selective ETA receptor antagonist BQ123. At an earlier embryonic stage, formation of pharyngeal arch arteries and endocardial cushion is disturbed in Edn1-/- homozygotes. In situ hybridization confirmed ET-1 expression in the endothelium of the arch arteries and cardiac outflow tract and the endocardial cushion as well as in the epithelium of the pharyngeal arches. Thus, ET-1 is involved in the normal development of the heart and great vessels, and circulating ET-1 and/or other ET isoforms may cause a functional redundancy, at least partly, through the ETA receptor.
authors.affiliation: Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kurihara
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: H
authors.initials: H
authors.lastname: Oda
authors.forename: K
authors.initials: K
authors.lastname: Maemura
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: T
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001013:Aorta, Thoracic / Q000002:abnormalities*; D016232:Endothelins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006345:Heart Septal Defects, Ventricular / Q000209:etiology*; D051379:Mice; D008813:Mice, Inbred ICR
chemical_list: D000911:Antibodies, Monoclonal; D016232:Endothelins