Jostling for position in angiogenic sprouts: continuous rearrangement of cells explained by differential adhesion dynamics

Abstract

Endothelial sprouting during angiogenesis is a highly coordinated morphogenetic process that involves polarized tip cells leading stalk cells to form new capillaries. While tip and stalk cells previously were thought to be stable and have static phenotypes within the sprout, it is becoming increasingly clear that endothelial cells undergo dynamic rearrangements. A new study using computer simulations, validated by in vitro and in vivo experimental data, now provides an explanation for these rearrangements, showing that sprouting cells are in a continuum of migratory states, regulated by differential cell-cell adhesions and protrusive activities to drive proper vascular organization.

Figure 1. Differential cell–cell adhesions and protrusion drive continuous endothelial rearrangement

Notch signaling and VEGFR-2 activity throughout angiogenic sprouts are heterogeneous and dynamic, which result in differential VE-cadherin junctional activity and a continuum of intercalated cellular rearrangement. Endothelial cells with active VEGFR-2 signaling and low Notch signaling (no shade) have weak cell–cell adhesion and polarized junctional-cortex protrusions (indicated by serrated VE-cadherin junctions and vesicles). In contrast, cells with high Notch signaling (darker shade) have straight junctions and inhibited protrusions due to immobile VE-cadherin junctions that promote strong cell–cell adhesion. Highly motile endothelial cells are propelled through the sprout via differential adherens junction dynamics between individual cells.