Tetralogy of fallot and alterations in vascular endothelial growth factor-A signaling and notch signaling in mouse embryos solely expressing the VEGF120 isoform

Circ Res. 2007 Mar 30;100(6):842-9. doi: 10.1161/01.RES.0000261656.04773.39. Epub 2007 Mar 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / abnormalities
  • Aorta, Thoracic / pathology
  • Disease Models, Animal
  • Embryo, Mammalian / abnormalities*
  • Embryo, Mammalian / metabolism
  • Embryo, Mammalian / pathology
  • Gene Expression Regulation, Developmental
  • Heart Ventricles / abnormalities
  • Heart Ventricles / pathology
  • Immunohistochemistry
  • In Situ Hybridization
  • Jagged-2 Protein
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Mutant Strains
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / metabolism
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • Tetralogy of Fallot / genetics*
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Jag2 protein, mouse
  • Jagged-2 Protein
  • Membrane Proteins
  • Notch1 protein, mouse
  • Protein Isoforms
  • RNA, Messenger
  • Receptor, Notch1
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Vascular Endothelial Growth Factor Receptor-2