Biomedical Engineering Reference
In-Depth Information
lopathies, degenerative disorders, tissue injury occurring in ischemia, or tumor
progression) conditions [64, 306].
In particular, vascular endothelial growth factors, VEGFs, which act as a
positive chemotactic guidance for ECs (as widely demonstrated in literature
[57, 66, 405], concomitantly mediate several calcium-dependent pathways. As
characterized in [32, 133, 135, 211, 285], VEGF molecules, binding to their
surface tyrosine kinase receptors, initiate a series of intracellular cascades,
which results in the indirect production of arachidonic acid (AA) and ni-
tric oxide (NO), as characterized in [133, 135]. Both these second messengers
bind to plasmamembrane sites, opening cation channels and allowing the in-
flux of extracellular calcium into the cytosol; see Figure 6.1. The process,
also called noncapacitative (or non-store-operated) calcium entry (NCCE or
NSOCE), causes localized and peripheral restricted accumulations of the ion
[390], which regulates important biophysical properties of ECs, such as their
intrinsic motility, elasticity, and chemotactic strength, ultimately enhancing
their migratory capacity, which is fundamental in the initial phases of the
vascular progression (see Figure 6.1 and refer to [32, 133, 135]), that will be
further analyzed in the following chapter.
Indeed, we here aim at systematically characterizing the relationships be-
tween Ca 2+ dynamics and selected cell migratory parameters (such as veloc-
ity and mean displacement) under different physiopathological conditions, as
well as to reproduce varying morphologies of the motile endothelial cell. To do
this, we simulate a simple and reliable motility assay with an EC (whose 3D
morphology is based on experimental images and characterized by a realistic
differentiation between the nucleus and the cytosolic region) placed on one
side of a three-dimensional chamber and stimulated by an exogenous VEGF
source. For instance, we focus on the model counterparts of biomedical ap-
proaches which, interfering with calcium machinery, are able to slow down
cell migration; such strategies, in fact, may represent a useful starting point
for pharmacological treatments that, inhibiting cell motion, have the poten-
tial to disrupt malignant neovascularization and, eventually, invasion. It is
finally useful to underline that the proposed model is referred to a specific
type of endothelial cell: the tumor-derived individual (TEC). TECs are iso-
lated and cultured from human carcinomas on the basis of membrane markers
and, whereas they display analogous calcium-dependent cascades with respect
to their \normal" counterpart, exhibit altered genotype, phenotype, and func-
tion. They are often aneuploid, display chromosomal instability and express
peculiar genes [56, 303, 359]. In addition, tumor-derived ECs avoid senes-
cence in vitro and show enhanced proliferation, motility and overexpression
of membrane receptors [21, 54, 55, 56, 170].
 
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