Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 207

1 Introduction

The endothelium—the inner lining of all blood vessels—is the main barrier that
actively regulates the exchange of water and solutes from the blood to the sur-
rounding tissues and vice versa. All tissues require a continuing supply of nutrients
and a means of clearing waste products. The vascular system is very well equipped
to this task. Capillaries are the most important sites for physiological exchange of
solutes and waste products, as they are sufficiently ''open'' (i.e., ''permeable'') to
allow the ready exchange of small molecule nutrients and waste products between
the blood and tissues [ 1 ], whereas pathological exchange (e.g under inflammatory
conditions) mainly occurs at the level of the post-capillary venules. Important
parameters that govern capillary permeability are: (1) vascular surface area
available for molecular exchange; (2) thickness of the vessel wall; (3) hydraulic
conductivity, a measure of capillary permeability to water; (4) reflection coeffi-
cient, a measure of solvent drag in relation to that of water; (5) diffusion; and
(6) trans-vascular pressure gradients [ 1 ].
It is important to distinguish between the basal permeability levels of normal
tissues and the greatly increased levels of plasma protein extravasation that occur
in pathology [ 2 ]. These hyperpermeable states may be acute or chronic and differ
from each other and from basal levels of permeability with respect to the vessels
that leak, the composition of the extravasate, and the anatomic pathways that
solutes follow in crossing vascular endothelium [ 1 ]. The contractility of the
venular endothelium has long been recognized and this endothelial activity

represents an important pharmacological target [ 2 - 4 ].
Breach of vascular integrity results in the accumulation of plasma, proteins and
cells in the interstitial space, and is one of the cardinal signs of the inflammatory
response [ 2 ]. Tight regulation of the vascular permeability barrier is required to
hold both acute and chronic inflammatory disease in check, and failure to restore
barrier function in a timely manner can result in a catastrophic loss of vascular
volume, as in septic shock, or contribute to the development of chronic inflam-
matory diseases such as atherosclerosis [ 5 ].
Vascular permeability is regulated by the coordinated opening and closing of
endothelial cell-cell junctions and relies on a complex interplay of junctional
adhesion components, cytoskeletal rearrangements, and cellular adhesive and
counter-adhesive forces [ 4 ].
The endothelium is exposed to a variety of chemical and mechanical factors.
Mechanical forces are exerted by blood flow and blood pressure. Blood flow creates a
frictional force on the endothelial surface known as shear stress, whereas blood
pressure creates (cyclic) stretching forces on the vessel wall, known as wall stress. On
top of these fluid forces, the vessel wall is locally subjected to stretch forces induced
by rhythmic distension of organs, such as a beating myocardium or a breathing lung.
In addition to these applied forces, other mechanical factors determined by the
cellular microenvironment are perceived by the endothelium as well, such as
geometry and rigidity of the extracellular matrix. Through mechanotransduction