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Cardiovascular Research Advance Access originally published online on December 18, 2007
Cardiovascular Research 2008 78(2):366-375; doi:10.1093/cvr/cvm108
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Developmental coronary maturation is disturbed by aberrant cardiac vascular endothelial growth factor expression and Notch signalling

Nynke M.S. van den Akker1, Vincenza Caolo2, Lambertus J. Wisse1, Patricia P.W.M. Peters2, Robert E. Poelmann1, Peter Carmeliet3,4, Daniël G.M. Molin1,2,{dagger} and Adriana C. Gittenberger-de Groot1,*,{dagger}

1 Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, PO Box 9600, 2300 RC Leiden, The Netherlands
2 Department of Physiology, CARIM, Maastricht University, Maastricht, The Netherlands
3 Center for Transgene Technology and Gene Therapy, K.U. Leuven, Leuven B-3000, Belgium
4 Department of Transgene Technology and Gene Therapy, VIB, Leuven B-3000, Belgium

* Corresponding author. Tel: +31 71 526 9301; fax: +31 71 526 8289. E-mail address: acgitten{at}lumc.nl

Aims: Currently, many potential cardiac revascularization therapies target the vascular endothelial growth factor (VEGF) pathway, with variable success. Knowledge regarding the role of the VEGF/Notch/ephrinB2 cascade in (ab)normal coronary development will provide information on the subtle balance of VEGF signalling in coronary maturation and might enhance our therapeutic possibilities.

Methods and results: The effect of VEGF isoforms on coronary development was explored in vivo using immunohistochemistry and RT–qPCR on Vegf120/120 mouse embryos solely expressing VEGF120. In vitro, human arterial coronary endothelial cells were treated with VEGF121 or VEGF165 upon which RT–qPCR was performed. In vivo, mutant coronary arterial endothelium showed a decrease in protein expression of arterial markers such as cleaved Notch1, Delta-like4, and ephrinB2 concomitant with an increase of venous markers such as chicken ovalbumin upstream promoter transcription factor II. The venous endothelium showed the opposite effect, which was confirmed on the mRNA level. In vitro, mRNA expression of arterial markers highly depended on the VEGF isoform used, with VEGF165 having the strongest effect. Also, coronary arteriogenesis was anomalous in the mouse embryos with decreased arterial and increased venous medial development as shown by staining for smooth muscle {alpha}-actin, Delta-like1, and Notch3.

Conclusion: We demonstrate that VEGF isoform-related spatiotemporal cardiac alterations in the VEGF/Notch/ephrinB2 cascade lead to disturbed coronary development. This knowledge can contribute to optimizing therapies targeting VEGF signalling by enabling balancing between angiogenesis and vascular maturation.

KEYWORDS Arteriogenesis; Cell differentiation; Coronary development; Developmental biology; Endothelial function

Time for primary review: 24 days

{dagger} These senior authors contributed equally to this research.


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