Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 208

systems, cells translate these mechanical stimuli into biochemical signals that control
multiple aspects of cell behaviour, including proliferation, differentiation and cel-
lular adhesion [ 6 ]. For many years, it has been recognized that changes in the
magnitude and direction of shear stress have profound effects on the adhesion of
endothelial cells to their sub-endothelial matrix as well as on the organization of
inter-endothelial cell-cell interactions, as reviewed elsewhere [ 7 ]. Similarly, stretch
also affects endothelial monolayer integrity, as is well-established based on the
vascular leak-inducing effects of the ventilator, which contributes to severe lung
injury in intensive care treatment, as reviewed elsewhere [ 8 ]. However, limited
information is available on whether changes in rigidity of the extracellular matrix
(ECM) might affect the integrity of the endothelial barrier. Knowledge about the
relationship between ECM stiffness and barrier function is of importance as blood
vessels progressively stiffen with aging [ 1 , 2 ]. This stiffening is exacerbated by risk
factors associated with common disorders such as diabetes, hypertension, cancer,
atherosclerosis and renal disease [ 3 - 7 , 9 , 10 ]. All these disorders are associated to
endothelial dysfunction and many of them with increased vascular permeability in
particular, suggesting that stiffening of the vascular wall might destabilize the
endothelial barrier.
Here we review recent findings that shed light on the relationship between
chemical and mechanical factors that regulate the maintenance of the endothelial
barrier. For information on the genetic interactions implicated in the maintenance
of vessel integrity the reader is referred to a list of the genes involved [ 11 ].
Detailed information on regulation of barrier dysfunction [ 2 ], the signal trans-
duction pathways involved [ 4 ] and its clinical implications [ 5 , 12 ] exist to which
the interested reader is referred.
2 Cell-Cell Junction Formation
VE-cadherin-based adherens junctions (AJs) and claudin-based tight junctions
(TJs) form a semipermeable endothelial barrier between the vessel lumen and
stroma. In contrast to blood-brain endothelial cells, in which the TJs form a
sealing belt, TJs in most other endothelia have a mosaic structure leaving space for
the passage of macromolecules. The AJs contribute largely to the barrier properties
of these latter endothelia through their interaction with the actin cytoskeleton.
VE-cadherin, a calcium-dependent adhesion protein mediating transhomophilic
interactions, localizes at cell-cell contacts, regulating the formation of adherens
junctions, and linking the site of the junction to the actin cytoskeleton.
The procedure by which endothelial cells establish their adherens junctions has
remained unclear for a long time. Recently, the dynamics of cell-cell junction
formation and the corresponding architecture of the underlying cytoskeleton were
nicely visualized by terrific imaging in cultured human umbilical vein endothelial
cells [ 4 ]. It was shown that the initial interaction between cells is mediated by
protruding lamellipodia. On their retraction, cells maintained contact through thin