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(Circulation Research. 2007;100:842.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform

Nynke M.S. van den Akker, Daniël G.M. Molin, Patricia P.W.M. Peters, Saskia Maas, Lambertus J. Wisse, Ronald van Brempt, Conny J. van Munsteren, Margot M. Bartelings, Robert E. Poelmann, Peter Carmeliet, Adriana C. Gittenberger-de Groot

From the Departments of Anatomy and Embryology (N.M.S.v.d.A., D.G.M.M., S.M., L.J.W., C.J.v.M., M.M.B., R.E.P., A.C.G.-d.G.) and Pediatric Intensive Care (R.v.B.), Leiden University Medical Center, The Netherlands; the Department of Physiology (D.G.M.M., P.P.W.M.P.), Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands; and the Center for Transgene Technology & Gene Therapy (P.C.), University of Leuven, Belgium.

Correspondence to Adriana C. Gittenberger-de Groot, PhD, Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail acgitten{at}lumc.nl

The importance of vascular endothelial growth factor-A (VEGF) and subsequent Notch signaling in cardiac outflow tract development is generally recognized. Although genetic heterogeneity and mutations of these genes in both humans and mouse models relate to a high susceptibility to develop outflow tract malformations such as tetralogy of Fallot and peripheral pulmonary stenosis, no etiology has been proposed so far. Using immunohistochemistry, in situ hybridization, and quantitative RT-PCR on embryonic hearts, we have shown spatiotemporal increase and abnormal patterning of Vegf/VEGF/(phosphorylated) VEGFR-2, (cleaved) Notch1, and Jagged2 in the outflow tract of Vegf120/120 mouse embryos. This coincides with hyperplasia of specifically the outflow tract cushions and a high degree of subpulmonary myocardial apoptosis that, in later stages, manifest as pulmonary stenosis and ventricular septal defects. We postulate that increase of VEGF and Notch signaling during right ventricular outflow tract development can lead to abnormal development of both cushion and myocardial structures. Defective right ventricular outflow tract development as presented provides new insight in the etiology of tetralogy of Fallot.

Key Words: tetralogy of Fallot • apoptosis • VEGF • Notch

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