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Nat Cell Biol. 2017 Aug;19(8):915-927. doi: 10.1038/ncb3555. Epub 2017 Jul 17.

Dll4 and Notch signalling couples sprouting angiogenesis and artery formation.

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Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Röntgenstrasse 20, D-48149 Münster, Germany.
Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany.
Max Planck Institute for Molecular Biomedicine, Flow Cytometry Unit, Röntgenstrasse 20, D-48149 Münster, Germany.
Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
University of California San Diego Medical Center, 9500 Gilman Drive, La Jolla, California 92093, USA.


Endothelial sprouting and proliferation are tightly coordinated processes mediating the formation of new blood vessels during physiological and pathological angiogenesis. Endothelial tip cells lead sprouts and are thought to suppress tip-like behaviour in adjacent stalk endothelial cells by activating Notch. Here, we show with genetic experiments in postnatal mice that the level of active Notch signalling is more important than the direct Dll4-mediated cell-cell communication between endothelial cells. We identify endothelial expression of VEGF-A and of the chemokine receptor CXCR4 as key processes controlling Notch-dependent vessel growth. Surprisingly, genetic experiments targeting endothelial tip cells in vivo reveal that they retain their function without Dll4 and are also not replaced by adjacent, Dll4-positive cells. Instead, activation of Notch directs tip-derived endothelial cells into developing arteries and thereby establishes that Dll4-Notch signalling couples sprouting angiogenesis and artery formation.

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