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Nat Cell Biol. 2017 Aug;19(8):928-940. doi: 10.1038/ncb3574. Epub 2017 Jul 17.

Endothelial Notch signalling limits angiogenesis via control of artery formation.

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Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, D-48149 Münster, Germany.
Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Muenster, D-48149 Muenster, Germany.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, USA.
University of Warsaw, Faculty of Biology, Ul. Miecznikowa 1, 02-096 Warsaw, Poland.
Institute of Anatomy and Vascular Biology, Westfälische Wilhelms-Universität Münster, Vesaliusweg 2-4, 48149 Münster, Germany.


Angiogenic sprouting needs to be tightly controlled. It has been suggested that the Notch ligand dll4 expressed in leading tip cells restricts angiogenesis by activating Notch signalling in trailing stalk cells. Here, we show using live imaging in zebrafish that activation of Notch signalling is rather required in tip cells. Notch activation initially triggers expression of the chemokine receptor cxcr4a. This allows for proper tip cell migration and connection to the pre-existing arterial circulation, ultimately establishing functional arterial-venous blood flow patterns. Subsequently, Notch signalling reduces cxcr4a expression, thereby preventing excessive blood vessel growth. Finally, we find that Notch signalling is dispensable for limiting blood vessel growth during venous plexus formation that does not generate arteries. Together, these findings link the role of Notch signalling in limiting angiogenesis to its role during artery formation and provide a framework for our understanding of the mechanisms underlying blood vessel network expansion and maturation.

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