Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 215

Compliant

Extracellular matrix rigidity Stiff

Fig. 3 Blood vessels stiffen as a consequence of aging, diabetes, atherosclerosis, and ischemic
heart diseases. A variety of mechanisms accounts for stiffening of the vessel wall, including
cross-linking of matrix components, collagen deposition, increased pericyte coverage and
atherosclerotic plaque formation. In addition, increased interstitial pressure as well as
(periodically) stretching the vessel wall will result in an increased effective stiffness as sensed
by the endothelial cells (green outlining)

degeneration have been appreciated for a long time [ 45 ]. Blood vessels stiffen as a
consequence of aging, diabetes, atherosclerosis, and ischemic heart diseases.
A variety of mechanisms accounts for stiffening of the vessel wall, including
cross-linking of matrix components [ 46 ], collagen deposition, increased pericyte
coverage [ 47 ] and atherosclerotic plaque formation (Fig. 3 )[ 45 ]. In addition,
increased interstitial pressure as well as (periodically) stretching the vessel wall
will result in an increased effective stiffness as sensed by the endothelial cells.
Recent data suggest a strong interaction between vascular wall stiffness and
vascular permeability [ 3 , 48 ]. The implications of vascular wall stiffening for other
vascular functions such as angiogenesis as will be covered in detail by Califano
and Reinhart-King elsewhere in this topic.
In response to substrate stiffening, endothelial cells in culture modify their
migration, morphology, spreading, and growth [ 49 ]. By virtue of these well known
effects, substrate stiffness is recognized as a powerful determinant of endothelial
form and function [ 44 ]. A key event in rigidity sensing is the modulation of
cellular contractility. Cells on soft materials exert lower forces than cells on stiff
materials, decreasing tension on force-bearing elements (Fig. 4 )[ 44 ]. Through an
as yet partially elucidated mechanism, stiffening results in elevated activity levels
of the small GTPase RhoA, mediating enhanced contractile forces [ 3 ]. These
responses are mediated by load-bearing subcellular structures, such as the cell-
adhesion complexes and the cytoskeleton. Recent work has demonstrated that
these structures are dynamic, undergoing assembly, disassembly [ 43 ]. Several
studies have shown that cell-cell contacts bear considerable forces [ 50 , 51 ] and,
undergo dynamic, myosin-dependent elongation [ 52 ]. Applied forces [ 50 ] and
stiffer substrata [ 53 ] enhance cell-cell contact assembly, indicating that these
adhesions also undergo force-dependent adhesion strengthening. There is also
evidence for actin flow along cell-cell contacts [ 54 ]. Vinculin is recruited to the
junctions in a myosin-dependent manner, thereby contributing to adhesion
strengthening [ 55 ]. Finally, a direct relationship between the total cellular traction