title: The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis.
abstract: Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.
authors.affiliation: 1] Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK [2].
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Claudio Areias
authors.initials: CA
authors.lastname: Franco
authors.affiliation: Centre for Computational Neuroscience and Robotics, Department of Informatics, University of Sussex, Brighton BN1 9QJ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Philippides
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Raquel
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Roentgenstr. 20 48149 Muenster, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dierkes
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gebala
authors.affiliation: Vascular Patterning Laboratory, VIB3-Vesalius Research Center & CMVB, Department of Oncology, KU Leuven Campus Gasthuisberg O&N4, Herestraat 49 box 912 B-3000 Leuven, Belgium.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stanchi
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Jones
authors.affiliation: Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Roentgenstr. 20 48149 Muenster, Germany.
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Cagna
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsv. 20 751 85 Uppsala, Sweden.
authors.forename: Simone
authors.initials: S
authors.lastname: Weström
authors.affiliation: Uppsala University, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjöldsv. 20 751 85 Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
authors.affiliation: Max-Planck-Institute for Molecular Biomedicine, Roentgenstr. 20 48149 Muenster, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.affiliation: 1] Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK [2] Vascular Patterning Laboratory, VIB3-Vesalius Research Center & CMVB, Department of Oncology, KU Leuven Campus Gasthuisberg O&N4, Herestraat 49 box 912 B-3000 Leuven, Belgium.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007365:Intercellular Junctions / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C467480:vascular endothelial growth factor A, mouse