Dll4 and Notch signalling couples sprouting angiogenesis and artery formation

Mara E Pitulescu; Inga Schmidt; Benedetto Daniele Giaimo; Tobiah Antoine; Frank Berkenfeld; Francesca Ferrante; Hongryeol Park; Manuel Ehling; Daniel Biljes; Susana F Rocha; Urs H Langen; Martin Stehling; Takashi Nagasawa; Napoleone Ferrara; Tilman Borggrefe; Ralf H Adams

doi:10.1038/ncb3555

Dll4 and Notch signalling couples sprouting angiogenesis and artery formation

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

Authors

Mara E Pitulescu¹, Inga Schmidt¹, Benedetto Daniele Giaimo², Tobiah Antoine¹, Frank Berkenfeld¹, Francesca Ferrante², Hongryeol Park¹, Manuel Ehling¹, Daniel Biljes¹, Susana F Rocha¹, Urs H Langen¹, Martin Stehling³, Takashi Nagasawa⁴, Napoleone Ferrara⁵, Tilman Borggrefe², Ralf H Adams¹

Affiliations

¹ Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Röntgenstrasse 20, D-48149 Münster, Germany.
² Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany.
³ Max Planck Institute for Molecular Biomedicine, Flow Cytometry Unit, Röntgenstrasse 20, D-48149 Münster, Germany.
⁴ 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.
⁵ University of California San Diego Medical Center, 9500 Gilman Drive, La Jolla, California 92093, USA.

PMID: 28714968
DOI: 10.1038/ncb3555

Abstract

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.

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Calcium-Binding Proteins
Cell Communication
Cell Differentiation
Cell Lineage
Cell Movement
Cell Proliferation
Cells, Cultured
Endothelial Cells / metabolism*
Female
Gene Expression Regulation
Genotype
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Jagged-1 Protein / genetics
Jagged-1 Protein / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice, Inbred C57BL
Mice, Transgenic
Neovascularization, Physiologic*
Phenotype
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism*
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism
Retinal Artery / cytology
Retinal Artery / metabolism*
Signal Transduction
Time Factors
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Adaptor Proteins, Signal Transducing
CXCR4 protein, mouse
Calcium-Binding Proteins
DLL4 protein, mouse
Intracellular Signaling Peptides and Proteins
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
Notch1 protein, mouse
Receptor, Notch1
Receptors, CXCR4
Vascular Endothelial Growth Factor A
vascular endothelial growth factor A, mouse