Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 216

Traction force

Cell-cell force

x

RhoA inact. RhoA act.

y

?

Fig. 4 Stiffening of the extracellular matrix induces an increased tension in endothelial
intercellular junctions. In endothelial monolayers forces are exerted at cell-matrix (traction
forces, indicated in red) and at cell-cell interactions (cell-cell forces indicated in blue). The
intercellular forces account for nearly one-half of the overall forces in the monolayer. These
forces are enhanced substantially with substrate stiffening. Through an as yet partially elucidated
mechanism[ 3 , 48 , 51 ], stiffening results in elevated activity levels of the small GTPase RhoA,
mediating enhanced contractile forces. The nature of the guanine exchange factors (GEFs) and
GTPase activating proteins (GAPs) remains to be identified

force on the ECM and the endogenous cell-cell force exists, such that the cell-cell
tension is a constant fraction of the cell-ECM traction [ 3 , 51 ].
Recent data indicate that stiffening of the endothelial microenvironment has a
profound role in regulation of endothelial monolayer integrity. Stiffening of the
extracellular matrix makes the endothelium more susceptible to hyperpermeability
responses (Fig. 5 ). In response to thrombin on a compliant matrix, endothelial cells
comprising the monolayer contract collectively, intercellular gaps do not form, and
the monolayer stays intact. In response to thrombin on stiffer matrices, cells
comprising the monolayer contract individually, large gaps arise between adjacent
cells, and the monolayer becomes severely disrupted. These disruptive effects on
stiffer substrates are promoted by larger physical force magnitudes [ 3 ]. Moreover,
stiffening of extracellular matrix within the intima promotes endothelial monolayer
permeability [ 48 ]. Similarly, the transendothelial transmigration of leukocytes also
increased with increasing ECM stiffness suggesting similar underlying mecha-
nisms [ 56 ]. A finding of particular interest is that these substrate stiffness-
dependent effects are mediated by basal force differences in the endothelial
monolayer.
In line with these findings, Ohayon et al. [ 57 ] demonstrated that, in addition to
low endothelial shear stress and cyclic stretch, enhanced arterial wall stiffness may
be a precondition for the initiation and development of atherosclerosis. These
authors investigated the contribution of a contracting myocardium to local rigidity
of the coronary arteries. It is well-known that elasticity of the coronary arterial
wall is highly nonlinear, since a small variation in stretch induces a large increase
in stress and wall stiffness. In this study very heterogeneous arterial wall stiffness
was observed, with specific regions of distinct rigidity, originating from the axial
distortion of the arterial wall caused by a contracting myocardium. Of particular