title: Synchronization of endothelial Dll4-Notch dynamics switch blood vessels from branching to expansion.
abstract: Formation of a regularly branched blood vessel network is crucial in development and physiology. Here we show that the expression of the Notch ligand Dll4 fluctuates in individual endothelial cells within sprouting vessels in the mouse retina in vivo and in correlation with dynamic cell movement in mouse embryonic stem cell-derived sprouting assays. We also find that sprout elongation and branching associates with a highly differential phase pattern of Dll4 between endothelial cells. Stimulation with pathologically high levels of Vegf, or overexpression of Dll4, leads to Notch dependent synchronization of Dll4 fluctuations within clusters, both in vitro and in vivo. Our results demonstrate that the Vegf-Dll4/Notch feedback system normally operates to generate heterogeneity between endothelial cells driving branching, whilst synchronization drives vessel expansion. We propose that this sensitive phase transition in the behaviour of the Vegf-Dll4/Notch feedback loop underlies the morphogen function of Vegfa in vascular patterning.
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ubezio
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Raquel Agudo
authors.initials: RA
authors.lastname: Blanco
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Vascular Patterning Laboratory, Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Ilse
authors.initials: I
authors.lastname: Geudens
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Vascular Patterning Laboratory, Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stanchi
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Vascular Patterning Laboratory, Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Martin L
authors.identifier: 0000-0003-0994-5652
authors.initials: ML
authors.lastname: Jones
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratories, London, United Kingdom.
authors.forename: Anan
authors.initials: A
authors.lastname: Ragab
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Vascular Biology Laboratory, London Research Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratories, London, United Kingdom.|Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium.|Department of Oncology, Vascular Patterning Laboratory, Vesalius Research Center, Katholieke Universiteit Leuven, Leuven, Belgium.|Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.|German Center for Cardiovascular Research, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Holger
authors.identifier: 0000-0002-3030-0384
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: agent based modelling; angiogenesis; computational biology; developmental biology; human; mouse; neovascularization; signalling dynamics; stem cells; systems biology