Abstract
Vascular endothelial cells (ECs) in angiogenesis exhibit inhomogeneous collective migration called “cell mixing”, in which cells change their relative positions by overtaking each other. However, how such complex EC dynamics lead to the formation of highly ordered branching structures remains largely unknown. To uncover hidden laws of integration driving angiogenic morphogenesis, we analyzed EC behaviors in an in vitro angiogenic sprouting assay using mouse aortic explants in combination with mathematical modeling. Time-lapse imaging of sprouts extended from EC sheets around tissue explants showed directional cohesive EC movements with frequent U-turns, which often coupled with tip cell overtaking. Imaging of isolated branches deprived of basal cell sheets revealed a requirement of a constant supply of immigrating cells for ECs to branch forward. Anisotropic attractive forces between neighboring cells passing each other were likely to underlie these EC motility patterns, as evidenced by an experimentally validated mathematical model. These results suggest that cohesive movements with anisotropic cell-to-cell interactions characterize the EC motility, which may drive branch elongation depending on a constant cell supply. The present findings provide novel insights into a cell motility-based understanding of angiogenic morphogenesis.
Highlights
Angiogenesis is a process of new blood vessel formation from pre-existing vessels by sprouting and intussusception[1,2]
As for angiogenic morphogenesis, leading the way has been thought to be an endothelial cells (ECs) called a ‘tip cell’, which responds to pro-angiogenic signals represented by vascular endothelial growth factor (VEGF) presents the Notch ligand delta-like ligand 4 (Dll4) to the following stalk cells[4,5,6,7,8]
It has been reported that the balance and dynamics of ongoing Dll4/Notch signaling between cells play an important role in the rearrangement of tip and stalk cells[14]
Summary
Angiogenesis is a process of new blood vessel formation from pre-existing vessels by sprouting and intussusception[1,2] It involves morphogenetic collective movement of endothelial cells (ECs), leading to branching networks by sprouting, elongation and bifurcation. Our recent deterministic models fit well some aspects of collective cell migration during angiogenesis[21,22], indicating the existence of prevailing cellular interaction which remains unclear This model incorporates distance-dependent attractive and repulsive two-body interactions into a one-dimensional Newtonian equation of motion defined by discrete equations. Giving cell density-dependent conditions for elongation and bifurcation, it successfully reproduces branching morphogenesis with cellular mixing and U-turn behavior This model has succeeded in explaining complex EC behaviors by cell-to-cell interactions based on simple Newtonian dynamics, the assumption of two-body interactions is not quantitatively validated. Anisotropic nature of the two-body interactions, which may be caused by cellular polarity, is not considered
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