Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1 - PubMed (original) (raw)

Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1

Y Kurihara et al. J Clin Invest. 1995 Jul.

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.

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Comment in

• Close encounters with ET-1.
  Chien KR. Chien KR. J Clin Invest. 1995 Jul;96(1):1-3. doi: 10.1172/JCI118008. J Clin Invest. 1995. PMID: 7615778 Free PMC article. No abstract available.

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