Tetralogy of Fallot and Alterations in Vascular Endothelial Growth ...

suggest that this myocardium is a distinct population critically
involved in proper positioning of the large OFT vessels.
46 Furthermore, increasing evidence is pointing toward a
link between alterations in SHF development and the etiology
of OFT anomalies including TOF. 15,16,44 We postulate that
this SHF-derived subpulmonary myocardium is highly sensitive
for VEGF and Notch signaling. The high levels of
apoptosis in this myocardial population probably lead to
hypoplasia of the pulmonary trunk and the often observed
right ventricular OFT stenosis. The occurrence of this phenotype
in our model is likely aggravated by the manifestation
of the earlier discussed cushion hyperplasia. Furthermore,
ablation of this SHF-derived myocardium, in our case by
apoptosis, might lead to alterations in proper positioning of
the OFT vessels leading to dextroposition of the aorta.
Abnormalities of the Pulmonary Arteries and
Aortic Arch
The development of vascular anomalies has been linked to
altered blood flow 47 and, as such, can develop secondary to
cardiac outflow defects. The high frequencies of pulmonary
vascular defects (ie, hypoplasia and atresia of the DA and
pulmonary arteries) in the Vegf120/120 mutant along with
right ventricular OFT obstruction is in agreement with this
assumption. The severe pulmonary outflow or arterial stenosis
will impair blood flow to the lungs. We suggest that this
leads to local hypoxia and development of collateral vessels
originating from the dorsal aorta, as observed in our mouse
model as well as in human neonates with severe pulmonary
stenosis. 48
The Vegf120/120 mouse model has been described as a
model with overt cardiovascular defects found in patients
with DiGeorge syndrome (ie, TOF, common arterial trunk,
and aortic arch interruption type B). However, the occurrence
of aortic arch malformations in this research seems to differ
slightly from earlier published data on this model. 5 This
might be explained by the differences in time points analyzed
between both studies. As in this research, embryos at several
different time points of development were investigated
(E10.5 to E19.5 versus E14.5/neonates), the number of
anomalies encountered here might be underestimated because
of ongoing development.
Conclusions
We conclude that during normal heart development, VEGF
and subsequent Notch signaling must be tightly controlled,
especially in the SHF-derived myocardium of the right
ventricular OFT. In the Vegf120/120 mice, local increase of
VEGF signaling in this region leads, likely via changes in the
Notch pathway, to hyperplasia of the OFT cushions and
apoptosis of the SHF-derived subpulmonary myocardium.
This working model might explain the development of TOF
in the human population as found in individuals with VEGF
and JAGGED1 mutations and 22q11 deletions. 20–22
Acknowledgments
We thank Jan Lens for preparation of the figures.
Van den Akker et al VEGF and Notch in TOF Development 7
Sources of Funding
N.M.S.v.d.A. was funded by The Netherlands Heart Foundation
grant 2001B057.
None.
Disclosures
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