Cohesive and anisotropic vascular endothelial cell motility driving angiogenic morphogenesis

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.

Pattern formation of elliptic particles by two-body interactions: a model for dynamics of endothelial cells in angiogenesis

“…In our previous work, we proposed a discrete dynamic model for the dynamics of ECs during angiogenesis on the basis of in vitro experiments [1,22], and verified that the deterministic two-body interaction between ECs can bring about cell-mixing, elongation, and branching [12]. In addition, we estimated parameters and confirmed validity of the model by comparing it with the movement of ECs on a two-dimensional plane obtained by in vitro experiments using mouse aortic tissue [23]. The results suggested the existence of attractive force in an area about the length of a pseudopod and repulsive force which works over shorter distances.…”

“…Reference values of other parameters were D = 16, R a = 1.5a, γ = 0.1, f a = 0.002, f r = 0.05, and f p = 0.005. Comparing with experimental situations [23], ab ∼ 2500 µm 2 , which implies that unit length is about 50 µm, and one time step of Eqs. ( 2)-( 4) is about 10 minutes.…”

“…In this paper, we present a discrete mathematical model for the dynamics of ECs during angiogenesis considering the shape of an EC on the basis of the results in [23]. Using the proposed model, we investigate the relationship between the shape of an ellipse and pattern formation.…”

Mechanical regulation of the early stages of angiogenesis

“…Tip cells lead the way and induce a 'stalk cell' phenotype in adjacent ECs to recruit them as followers in the sprout [55], as opposed to the 'phalanx cells', which stay in the original vessel. Interestingly, cell phenotype can change during elongation with tip and stalk cells often switching roles [73][74][75][76]. While tip cells spearheading the sprout exhibit an enhanced migratory phenotype with numerous filopodia [58], stalk cells rely on an increased proliferation rate to guarantee the continuity of the network [77,78].…”

Fatty Acid Metabolism in Endothelial Cell

“…ECs lining the inner blood and lymphatic vessels are essential for the vascular system [1,2]. In adults, ECs remain quiescent for years but still retain the capacity to switch rapidly from quiescent cells to activated sprout cells to initiate new vessel formation(angiogenesis) under certain conditions such as inflammation or injury [3,4]. This tightly regulated process starts with the migratory tip cells and is followed by proliferating stalk cells until new vessel sprouts are created.…”