Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: Implications for modulating arteriogenesis and angiogenesis

Zhao-Jun Liu, Takashi Shirakawa, Yan Li, Akinobu Soma, Masahiro Oka, G. Paolo Dotto, Ronald M. Fairman, Omaida C Velazquez, Meenhard Herlyn

Research output: Contribution to journalArticle

360 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14-25
Number of pages12
JournalMolecular and Cellular Biology
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor A
Endothelial Cells
Ligands
Gene Expression
Phosphatidylinositol 3-Kinase
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2
src-Family Kinases
Angiogenesis Inducing Agents
Vascular Endothelium
Fibroblast Growth Factor 2
Mitogen-Activated Protein Kinases
Blood Vessels
Intercellular Signaling Peptides and Proteins
Phenotype
delta protein
matrigel

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells : Implications for modulating arteriogenesis and angiogenesis. / Liu, Zhao-Jun; Shirakawa, Takashi; Li, Yan; Soma, Akinobu; Oka, Masahiro; Dotto, G. Paolo; Fairman, Ronald M.; Velazquez, Omaida C; Herlyn, Meenhard.

In: Molecular and Cellular Biology, Vol. 23, No. 1, 01.01.2003, p. 14-25.

Research output: Contribution to journalArticle

Liu, Zhao-Jun ; Shirakawa, Takashi ; Li, Yan ; Soma, Akinobu ; Oka, Masahiro ; Dotto, G. Paolo ; Fairman, Ronald M. ; Velazquez, Omaida C ; Herlyn, Meenhard. / Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells : Implications for modulating arteriogenesis and angiogenesis. In: Molecular and Cellular Biology. 2003 ; Vol. 23, No. 1. pp. 14-25.
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