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.

A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue

“…First of all, we have assumed that tip cells maintain their fate for the duration of the entire vascular elongation or until anastomosis events. However, it is useful to underline that few recent in vivo and in vitro studies have shown that, at least in some situations, a dynamic and continuous phenotypic interchange between stalk and tip individuals may also occur [3,5,28]. The hypotheses underlying the role played by the two VEGF isoforms are of course a simplified setting of the "real" physiological picture, although they are commonly accepted and used in the computational literature.…”

ARHGAP18: an endogenous inhibitor of angiogenesis, limiting tip formation and stabilizing junctions

“…[8][9][10] Recently, it has been shown that these TC and SC phenotypes are in fact transient states and the cells are constantly reshuffling positions. 9,11 Dynamic transitioning of TC and SC fates and positions is essential for effective patterning and expansion of the vascular network and is dependent on differential Dll4 expression and reorganization of the cell-cell junctions. 2,9,11 Under physiological conditions, the angiogenic response is tightly controlled suggesting the existence of negative regulators that limit or restrict tip cell formation.…”

A non-canonical Notch complex regulates adherens junctions and vascular barrier function

“…Identifying ways to isolate the cortical from transcriptional pathway of Notch may provide new opportunities to control these devastating complications. Furthermore, quantitative differences in expression of Notch and Dll4 in different vascular beds, described as a key mechanism for tip/stalk cell specification in angiogenesis 30 , may underlie differences in shear sensitivity and baseline permeability in organ-specific vascular beds. More broadly, the combination of a non-canonical pathway that regulates adhesive and cytoskeletal processes together with a transcriptional regulator of cell fate programs, channeled through a single receptor, provides a new framework for understanding coordinated developmental programs such as stem cell differentiation and tissue morphogenesis.…”