Computational Modeling of Angiogenesis: Towards a Multi-Scale Understanding of Cell–Cell and Cell–Matrix Interactions - Mechanical and Chemical Signaling in Angiogenesis - page 166

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Fig. 2 Overview of the computational models of angiogenic sprouting. a Shows corneal
angiogenesis as modeled in the discrete model based on tip cell elasticity and stalk cell
adhesion [ 8 ]. b Shows the networks formed with the discrete model with chemotaxis and
fibrinectin induced haptotaxis [ 6 ]. c Shows sprouting induced by preferential attraction to
elongated structures in a cell-based model [ 10 ]. d Shows the outcome of the cell-based model of
sprouting angiogenesis in a heterogeneous ECM [ 11 ]. e Illustrates how contact inhibition induces
sprouting in the cell-based chemotaxis model [ 14 ]. f Shows how tip cells form sprouts in the
agent-based tip cell selection and sprouting model [ 12 ]. All images were reproduced with the
publishers permission

that low fiber density results in cell elongation. Similar changes were observed
when the random fibers were replaced by a specific fiber pattern, for example long
fibers cause cells to elongate in the same direction as the fibers. The authors
propose that contact guidance, due to cell-matrix interactions, is key to role in
vascular sprouting because it enables sprout branching in an inhomogeneous
matrix.
Another model suggests branching can occur in the absence of matrix hetero-
geneity [ 14 ]. The model assumes cells are attracted towards an autocrine
chemoattractant, using similar rules as in chemotaxis-based network model ( Sect.
2.1 ). Contact inhibition mediated by VE-cadherin causes cells to be only sensitive
to the chemoattractant at positions of the cell membrane adjacent to the ECM.
Sprouting occurs in two ways. First, when cells are arranged in an aggregate, only
the outer layer of cells sense the chemoattractant. These cells tend to migrate
towards the center of the aggregate causing a buckling instability that induces
sprouting. This effect enables cells, even those with a low motility, to move against
the chemotactic gradient. Second, another mechanism may explain sprouting for