Matrix Mechanics and Cell Contractility in Angiogenesis - Mechanical and Chemical Signaling in Angiogenesis - page 152

5.1 Traction Forces Remodel Collagen and Fibronectin ECM
Early experiments indicate that ECs in confluent monolayers generate tension that
elevates webs of ECM above the cell monolayer that support spontaneous capillary
network formation [ 59 ]. Similarly, ECs and smooth muscle cells form networks
only after the appearance of organized basement membrane matrix [ 93 ]. Specifi-
cally, ECs synthesize and organize collagen into cables that promote spindle-
shaped morphologies and network formation, a response that requires traction
forces [ 58 ]. These data suggest that matrix remodeling is requisite for network
assembly.
The fibronectin ECM may be particularly important for mediating angiogenesis.
In 3D fibrin matrices, EC tubulogenesis requires the fibrillogenesis of a fibronectin
matrix that promotes cytoskeletal organization and tension [ 94 ]. Fibronectin
assembly increases intracellular stiffness that helps ECs match the stiffness of the
surrounding matrix during vessel formation. Separate studies indicate that ECs form
capillary-like structures with a central lumen atop tendrils of fibronectin [ 36 ]. In 2D,
fibronectin polymerization is requisite for the maintenance of stable cell-cell
interactions during network assembly [ 11 ]. Interestingly, fibronectin is assembled
into fibrils by cells [ 95 ] through endogenous Rho-mediated contractility, and
fibronectin fiber orientation is subsequently guided by traction forces [ 96 ]. These
interactions are sensitive to cell-cell interactions. Cadherin-mediated cell-cell
adhesions mediate cellular contractility that directs fibronectin fibril formation [ 97 ].
During Xenopus morphogenesis, cell-cell adhesions transfer tension to integrins that
direct fibronectin fibril formation in the blastocoel roof. These data suggest that EC
contractility, traction forces, and cell-cell interactions enable fibronectin ECM
assembly that is requisite for network assembly during angiogenesis.
6 Conclusion
Matrix stiffness and cell contractility are important regulators of cell shape and
growth, network assembly, EC mechanics, and ECM remodeling. While it is clear
that the mechanical microenvironment mediates angiogenesis, much work remains
to understand its ramifications. Future work should focus on 3D constructs that
recapitulate the endothelial microenvironment. In addition to the role of matrix
stiffness, the role of other mechanical cues (e.g. traction forces generated by
supporting cells; exogenous forces such as shear stress) will better elucidate the
complex interplay between the mechanical microenvironment and angiogenesis.
The clarification of the role of the mechanical microenvironment on angiogenesis
in vivo will better our understanding, and enable our control, of blood vessel
formation.