Matrix Mechanics and Cell Contractility in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 149

Fig. 4 Examples of EC network assembly. a ECs in culture are capable of forming networks that
mimic the morphology of capillaries in vivo (sketch from [ 58 ] with permission). ECs form networks
on compliant fibrin gels b (from [ 60 ] with permission), within collagen gels c (from [ 64 ] with
permission), or on polyacrylamide substrates d (from [ 11 ] with permission). Note the typical ring-
like morphologies of ECs despite substrate material. Double-headed arrows in b denote tubular
structures, scale bar is 250 lm; arrow in c points to a lumen-like region, scale bar is 25 lm; circles in
d outline sprouting cells that will make an additional cell-cell connections
network assembly is modulated by substrate stiffness alone [ 11 ], independent from
changes in ligand density. Interestingly, EC network assembly is induced on stiff
matrices by reducing the concentration of the surface-bound ligand [ 11 ]. These
findings suggest that EC network formation results from a balance of cell-cell and
cell-matrix interactions in order to optimize mechanical input to the cell [ 65 ]. On
compliant substrates where cell-substrate resistivity is reduced, ECs may seek out
additional mechanical input from interactions with adjacent cells that result in the
formation of networks. In contrast, stiff substrates may provide adequate
mechanical input to cells thus reducing a propensity to seek cell-cell interaction.
As networks form, ECs sprout to form additional cell-cell connections. This
response is also sensitive to matrix stiffness. Vascular sprouting of ECs embedded
in 3D fibrin gels decreases as matrix density increases, a response that can be
recovered in stiffer matrices by the addition of mesenchymal stem cells that
promote matrix metalloproteinase (MMP) upregulation [ 66 ]. VEGF-induced
sprouting in 3D is further regulated by matrix density and stiffness according to a
Goldilocks principle: intermediate matrix is ideal for sprouting while low density