Understanding cell rearrangement during angiogenic sprouting

19 June 2014

Endothelial cells show surprising cell rearrangement behavior during angiogenic sprouting. However, the underlying mechanisms and functional importance of this remain unclear. Katie Bentley and Holger Gerhardt from the LRI, Cancer Research UK, (KB now at BIDMC Harvard Medical School) and the VIB Vesalius Research Center, KU Leuven, were able to demonstrate that differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. Their results provide a mechanistic concept of how cells rearrange during normal sprouting and how this rearrangement switches to generating abnormal vessels in pathologies.

Why did you start investigating the interplay between VE-cadherin, Notch and VEGF signaling
during endothelial cell rearrangements and how did you proceed?
Holger: In 2010, we published a paper in Nature Cell Biology in which we described for the first time that endothelial cells dynamically competed for the leading position in each new blood vessel sprout under influence of VEGF and Notch. During that research, we also made the surprising discovery that endothelial cells swapped positions in an amazing way during blood vessel formation. Why and how they did this was unclear. This is where the current work started. We wondered what might be propelling endothelial cells during the ‘shuffling’ motion and how Notch might be  regulating this.

What is the impact of your findings?
Katie: Our findings highlight that local differences in adhesion between neighboring endothelial
cells drive the rearrangements, and that the loss of differences has a dramatic impact on vessel
patterning with the cells losing the ability to rearrange. The focus on local differences brings
about an important change of perspective: instead of considering the effects of global loss or gain
of function, as most current genetic studies do, a critical function of a gene of interest may rather lie in the differential regulation amongst a pool of cells. There is also a big impact for the simulation community – this work provides a key example that simulations can be predictive and drive new research directions in cell biology when integrated and validated against new in vivo data. Indeed the impact reaches beyond theoretical biology – this study serves as an example to all
agent modeling fields of the fact that new collective dynamics of real systems can be uncovered by
exploiting simulation.

You achieved these results by collaborating with international researchers and groups.Who were they?
Holger: We collaborated with Dietmar Vestweber (Muenster, Germany), an expert on VE-cadherin and its regulation; Lena Claesson-Welsh in Uppsala, Sweden, a leading scientist in endothelial cell
signaling; and Andrew Phillipides, University of Sussex, UK, an expert in image analysis of collective adaptive systems. Our team is part of a joint venture between the London Research Institute and VIB, and this interdisciplinary network of basic biologists, computational scientists, physicists and more clinically oriented scientists enabled us to combine the fundamental aspects of endothelial cell behavior with the study of pathological models.

Bentley et al.Nature Cell Biology, 2014

 


Holger Gerhardt (in the middle of the top row) and his team



Katie Bentley