Matrix Mechanics and Cell Contractility in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 150

promotes uncoordinated migration and high density promotes lack of sprout
elongation [ 67 ]. In addition, EC protrusions (lamelipodia, filopodia, microspikes)
extend preferentially from regions of greatest traction forces [ 68 ]. These data
indicate that matrix stiffness mediates a sprouting phenotype and suggest that
cytoskeletal tension contributes to sprouting decisions in ECs.
4.2 Supporting Cell Types Enable EC Network Assembly
in Stiff Matrices
Angiogenesis in vivo is dependent on supporting cells [ 69 ], and co-culture models
have begun to elucidate the mechanical role of support cells, such as fibroblasts or
stem cells, in EC capillary formation.
ECs invade 3D fibrin gels but do not form capillaries unless they are
co-cultured with mesenchymal stem cells (MSC) or fibroblasts [ 70 ]. Specifically,
adipose-derived stem cells (ASC) promote angiogenesis via the plasmin axis of
serine proteases, while bone marrow-derived stem cells utilize MMPs [ 70 ]. Pro-
motion of EC angiogenesis by association with ASCs is similar to results found
with fibroblasts that promote angiogenesis by exhibiting the angiogenic cytokines
urokinase plasminogen activator, hepatocyte growth factor, and tumor necrosis
factor alpha [ 71 ]. When ECs are cocultured with mesenchymal cells, the formation
of impermeable vessels is greatly enhanced in vitro, [ 72 ]. Importantly, such
prevascularized tissue constructs have been shown to accelerate anastomoses and
promote tissue remodeling after implantation in vivo [ 73 ].
While these results suggest that EC angiogenesis in coculture is dependent on
chemical signaling from supporting cells, evidence implicating the mechanical stiff-
ness of the 3D construct as a mediator of angiogenesis is emerging. For example, when
ECs are embedded in 3D fibrin gels with a monolayer offibroblasts seeded on top of the
gel, changes in ECM density alter matrix mechanics and EC traction force generation
that influence capillary morphogenesis [ 74 ]. Increasing the density of fibrin gels
inhibits capillary morphogenesis without the addition of such supporting cells [ 66 ].
This response is also established in vivo in SCID mice, where increasing fibrin matrix
density inhibits vascular formation that can be partially recovered with the addition of
MSCs [ 75 ]. While the role of the mechanical properties of 3D constructs on angio-
genesis is still emerging, these findings suggest that the mechanical interplay between
ECs and supporting cells is a critical regulator of angiogenesis in 3D.
4.3 Matrix Stiffness and Cell Contractility Alter EC Migration
Inherent to cell-cell interactions during angiogenesis is the ability of ECs and
vascular cells to migrate. It is well established that endogenous traction forces