Barrier Maintenance in Neovessels - Mechanical and Chemical Signaling in Angiogenesis - page 214

3.3.2 Fibroblast Growth Factor
FGF signaling is directly required for maintenance of inter-endothelial adhesion.
Suppression of FGF signalling leds to the dissociation of junctional adhesions in
both arterial and venous vascular beds [ 36 ]. Murakami et al. [ 37 ] found that
stimulation of endothelial monolayers with FGF1 increased p120- catenin-VE-
cadherin interaction, whereas inhibition of FGF signaling induced uncoupling of
p120-catenin from VE-cadherin, leading to VE-cadherin internalization [ 37 ]. The
association of p120-catenin at the VE-cadherin juxtamembrane domain is known
to inhibit VE-cadherin internalization by interfering with its binding to adaptor
proteins of the clathrin-mediated endocytic pathway [ 38 ]. Therefore, the loss of
endothelial barrier integrity in the absence of FGF signalling could be explained
by destabilization of VE-cadherin homophilic adhesion and subsequent dissocia-
tion of AJs.
3.3.3 Sphingosine-1-Phosphate (S1P)
S1P, a sphingolipid metabolite found in high concentrations in platelets and blood,
is a lipid mediator that interacts with GPCRs (S1P1-S1P5) to induce a variety of
biological responses [ 39 ]. It is also able to enhance endothelial barrier integrity
through S1P1 receptor (Edg1) signaling by promoting Rac1 activation and adherens
junction assembly [ 40 ]. In confluent human umbilical vein endothelial cells, S1P
significantly increases the abundance of VE-cadherin and ß-catenin at the cell-cell
contact regions and enhances AJ assembly [ 41 ]. Administration of the S1P receptor
agonist FTY720 in vivo potently blocks VEGF-induced vascular permeability,
suggesting that S1P receptor on endothelial cells is able to regulate vascular
permeability [ 42 ]. Furthermore, the S1P1 receptor is essential for normal vascular
function since systemic antagonism of S1P1 receptor under basal physiological
conditions causes S1P1 receptor internalization and degradation through receptor
phosphorylation, leading to enhanced pulmonary vascular leakage.
3.4 Regulation by the Local Microenvironment
There is growing recognition that—in addition to chemical factors such as vaso-
active agents and adhesion molecules residing in the extracellular matrix (ECM)—
mechanical factors, such as applied forces or the rigidity of the ECM, are able to
crucially direct the form and function of cells in general and of vascular cells in
particular [ 43 , 44 ]. Consequently these mechanical factors modulate blood vessel
morphology and function. Whereas the effects of shear and stretch forces have
been studied in detail, remarkably less is known about the role of ECM rigidity in
regulation of vascular barrier integrity. This is even more surprising, as the pro-
found effects of stiffening of the vascular wall as a major cause of cardiovascular