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(Circulation Research. 2004;95:1109.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Transforming Growth Factor ß–SMAD2 Signaling Regulates Aortic Arch Innervation and Development

Daniel G.M. Molin, Robert E. Poelmann, Marco C. DeRuiter, Mohamad Azhar, Thomas Doetschman, Adriana C. Gittenberger-de Groot

From the Department of Anatomy and Embryology (D.G.M.M., R.E.P., M.C.D., A.C.G.-d.G.) Leiden University Medical Center, Leiden, the Netherlands; and the Department of Molecular Genetics, Biochemistry and Microbiology (M.A., T.D.), University of Cincinnati, College of Medicine, Cincinnati, Ohio.

Correspondence to Prof A.C. Gittenberger-de Groot, Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9602, 2300 RC Leiden, The Netherlands. E-mail acgitten{at}lumc.nl

Aortic arch interruptions in humans and animal models are mainly caused by aberrant development of the fourth pharyngeal arch artery. Little is known about the maturation of this vessel during normal and abnormal development, which is the subject of this study. Tgfß2 knockout mice that present with fourth artery defects have been associated with defective neural crest cell migration. In this study, we concentrated on pharyngeal arch artery development during developmental days 12.5 to 18.5, focusing on neural crest cell migration using a Wnt1-Cre by R26R neural crest cell reporter mouse. Fourth arch artery maturation was studied with antibodies directed against smooth muscle -actin and neural NCAM-1 and RMO-270. For diminished transforming growth factor ß (TGF-ß) signaling, SMAD2 and fibronectin have been analyzed. Neural crest migration and differentiation into smooth muscle cells is unaltered in mutants, regardless of the cardiovascular defect found; however, innervation of the fourth arch artery is affected. Absent staining for nuclear SMAD2, NCAM-1, and RMO-270 in the fourth artery in mutant coincides with severe defects of this segment. Likewise, fibronectin expression is diminished in these cases. From these data we conclude the following: (1) neural crest cell migration is not a common denominator in cardiovascular defects of Tgfß2^–/– mice; (2) fourth arch artery maturation is a complex process involving innervation; and (3) TGF-ß2 depletion diminishes SMAD2-signaling in the fourth arch artery and coincides with reduced vascular NCAM-1 expression and neural innervation of this artery. We hypothesize that disturbed maturation of the fourth pharyngeal arch artery, and especially abrogated vascular innervation, will result in fourth arch interruptions.

Key Words: vascular innervation • neural crest • NCAM • SMAD • embryo

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