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Molecular and Cellular Biology, January 2003, p. 14-25, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.14-25.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of Notch1 and Dll4 by Vascular Endothelial Growth Factor in Arterial Endothelial Cells: Implications for Modulating Arteriogenesis and Angiogenesis

Zhao-Jun Liu,1,2 Takashi Shirakawa,1 Yan Li,1 Akinobu Soma,1 Masahiro Oka,1 G. Paolo Dotto,3 Ronald M. Fairman,2 Omaida C. Velazquez,1,2 and Meenhard Herlyn1*

The Wistar Institute,1 Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 021293

Received 19 June 2002/ Returned for modification 24 July 2002/ Accepted 4 October 2002

Notch and its ligands play critical roles in cell fate determination. Expression of Notch and ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the Notch pathway have suggested a critical role for Notch signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling that controls Notch and ligand gene expression is unknown. We show here that vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src tyrosine kinase. Constitutive activation of Notch signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model, whereas blocking Notch signaling can partially inhibit network formation. This study provides the first evidence for regulation of Notch/Delta gene expression by an angiogenic growth factor and insight into the critical role of Notch signaling in arteriogenesis and angiogenesis.

* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: (215) 898-3950. Fax: (215) 898-0980. E-mail: herlynm{at}wistar.upenn.edu.

Molecular and Cellular Biology, January 2003, p. 14-25, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.14-25.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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