The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis
Authors
- K. Bentley
- C.A. Franco
- A. Philippides
- R. Blanco
- M. Dierkes
- V. Gebala
- F. Stanchi
- M. Jones
- I.M. Aspalter
- G. Cagna
- S. Weström
- L. Claesson-Welsh
- D. Vestweber
- H. Gerhardt
Journal
- Nature Cell Biology
Citation
- Nat Cell Biol 16 (4): 309-321
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.