Biomedical Engineering Reference
In-Depth Information
significant attention has been paid to investigating the role of chemical events that
initiate and affect angiogenesis, e.g. paracrine and autocrine growth factor sig-
naling, the role of the mechanical environment in mediating angiogenesis is not as
well described.
Endothelial cells (ECs) reside in a complex mechanical environment that
consists of exogenous forces applied to cells, endogenous forces generated by
cells, and the local stiffness of the extracellular matrix (ECM) [ 2 ]. Exogenous
forces include the effects of hemodynamic forces due to blood flow (shear stress
[ 3 , 4 ], cyclic strain [ 5 , 6 ] and pulsatile pressure [ 7 ]), and forces applied by other
cell types (e.g. transmigrating leukocytes [ 8 ]) or tissues [ 9 ] as described in other
chapters within this topic. In addition to exogenous forces, the mechanical envi-
ronment of angiogenesis also includes the endogenous forces generated by ECs
against their ECM, more commonly referred to as cellular contractility and traction
stresses.
In this chapter we will describe how the mechanical environment influences
angiogenesis by exploring how matrix stiffness and cellular contractility mediates
EC behaviors that enable the progression of angiogenesis. Specifically, we will
discuss how matrix stiffness alters EC shape, contractility, proliferation, cell-cell
interactions, and cell-matrix remodeling.
2 Endothelial Cell Shape, Contractility, and Growth
Cell-ECM interactions control EC behaviors such as adhesion, spreading, and
growth that are crucial for the process of angiogenesis [ 10 ]. These responses are
facilitated by actomyosin interactions that generate cellular contractility regulated
in part by the Rho family of GTPases. In general, Rho-Kinase (ROCK) is activated
by GTP-bound Rho and alters the activity of myosin light chain kinase, an effector
of cell contractility. These interactions are sensitive to the stiffness of the extra-
cellular environment and govern changes in EC spreading and growth.
2.1 Matrix Stiffness Alters Endothelial Cell Spreading
and Contractility
Endothelial cell spreading and shape is directed by the mechanical microenvi-
ronment. Endothelial cell spread area increases with increasing substrate stiffness
[ 11 , 12 ]. On compliant substrates, ECs adopt a spindle shaped bipolar morphology,
while EC shape on stiffer substrates is more multipolar and isotropic [ 13 ]. Changes
in EC shape are accompanied by alterations in the density of focal adhesions,
clusters of integrins and adaptor proteins that anchor actin stress fibers to the
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