Angiogenesis and Percolation theory
Looking at angiogenesis through
a new point: Percolation theory
Nourozpour A, Mehdizadeh AR, Fazelzadeh A
Sadra–Sina Interdisciplinary Research Group
Mashad University of Medical Sciences
Abstract
Angiogenesis includes sprouting of
capillary wall and formation of vascular
tubes between pre-existing vessel and a
demand area. Regardless mechanisms
stimulating this process, a new sprout
tip must migrate through surrounding
media of a pre-existing vessel to its
target. The migration of sprout tip
through low-resistant pathways of its
surrounding media is similar to flow of
fluid through a porous media. To
predict the pathway of fluid flow
through a porous media, theories used
in other branch of sciences could be
applied for angiogenesis too. One of
these theories is Percolation theory
which is applied to predict the
probability of existing an open pathway
between two media by regarding the
24
structure of the media through which
fluid flows.
The probability of existing an open
pathway through which sprout tip
migrates and then, formation of a
linking tube between pre-existing vessel
and a demand area (angiogenesis),
depends on structure of surrounding
media of pre-existing vessel.
Local structure of surrounding media of
a cell influences migration routes for it,
like tip endothelial cell (EC) during
angiogenesis. Changing this structure to
a more solid or porous media affects
provided routes for EC migration. A
solid media do not allow angiogenesis
to progress, like the fovea of the eye. In
contrast, a media with more open
pathways facilitates migration of sprout
tip and angiogenesis, like destruction of
neurons and glial cells in diabetic
1386 ‫ زﻣﺴﺘﺎن‬- 38 ‫ﺷﻤﺎره‬

retinopathy by which more open its derivatives such as glycoproteins and

pathways around blood vessel arises to
facilitate angiogenesis.
By making more or fewer pathways
within a media one can facilitate or
inhibit sprout tip migration and also,
anastomosis with other branches.
Keywords: Angiogenesis, sprouting,
Percolation theory.
Introduction
Angiogenesis is a complex process that
includes the activation, proliferation,
and migration of endothelial cells (EC),
formation of vascular tubes and
networks, and linkage to the pre-
existing vascular networks (1).
This process is implicated in some
conditions, summarized in Table 1.
Among these extensive investigations,
most of them have focused on
stimulation of new sprout formation or
inhibition of it but a little attention to
other aspects of these processes has
been paid.
One of these aspects is the shape of new
vessels, their branching, their
anastomosis and their remodeling.
Formation of connecting pathways
between pre-existing vessels and a
demand area such as a solid tumor must
be through a media which is composed
of extracellular matrix (ECM)
components and different cells in ECM.
ECM is composed of two basic
components. First are the proteins and
proteoglycans. Second is water and
soluble substances. EC at the tip of the
new sprout must migrate among these
cells and high molecular weight (HMW)
components of ECM, like collagen
fibers and glycoproteins and
proteoglycans, to achieve their targets.
Thus it must migrate through pathways
that have lower resistance against their
movement, Figure 1. The shape of fixed
structures of this media between a pre-
existing vessel a solid tumor, like HMW
components of ECM and cells in ECM,
determines the pathways through which
EC can migrate easily and by this way,
the final shape of newly formed vessels
can be predicted. Migration of EC
through this media which has some
lower resistant pathways to migration is
similar to flow of fluid through a porous
media, Figure 2 (9).
From this point of view, theories which
were used in other branch of sciences
especially in Physics, mathematics and
engineering to predict the path way of
fluid flow through a porous media (10)
could be applied for angiogenesis too.
One of the most applicable methods is
Percolation theory, as discussed below.
Percolation theory: A representative
question (and the source of the name) is
as follows. Assume we have some
porous material and we pour some
liquid on top. Will the liquid be able to
make its way from hole to hole and

Table 1. Some pathologic conditions in which angiogenesis may be involved.

Conditions in which angiogenesis must Conditions in which angiogenesis must get

get stimulated. inhibited.
Myocardial ischemia3 Tumor growth4
Peripheral ischemia2 Diabetic retinopathy5,6
2
Wound healing Retinopathy of prematurity6
Rheumatoid arthritis7
Atherosclerotic plaques8

25
 Angiogenesis and Percolation theory

Figure 1. Histological organization of the retina. a-c In mice, retinal vessels arise from the optic nerve
around birth then extend radially in the superficial retina over 7-10 days to reach the periphery. d-f, similar
distribution of neurons, blood vessels and glia in a mouse retina. arrow indicates the optic nerve. d,
Radially orientated ganglion cell axons (labelled blue for leptin receptor) exit the eye through the optic
nerve (arrow). e, Fluorescent dextran (red) angiogram of adult retina; blood vessels also radiate from the
optic nerve (white arrow) to the periphery. f, Retinal astrocyte meshwork labelled for glial fibrillary acidic
protein (green) resembling that of blood vessels. g-h, Schematic representation of possible pathways (grey)
through which sprout tip from parent capillary wall can migrate. Grey routes indicate low resistant
pathways among fixed structures (black) of a media surrounding a parent capillary vessel. These pathways
function as tracks for migration of sprout tip. Final morphology of vascularization is mimicry of possible
pathways for tip migration.

reach the bottom? We model the As is quite typical, it is actually easier

physical question mathematically as a
three-dimensional network of n points
(or vertices) the connections (or edges)
between each two neighbors may be
open (allowing the liquid through) with
probability p, or closed with probability
1–p, and we assume they are
independent. We ask for a given p, what
is the probability that an open path
exists from the top to the bottom?
Mostly we are interested in the behavior
for large n.
to examine infinite networks than just
large ones. In this case the
corresponding question is “does an
infinite open cluster exists?” That is, is
there a path of connected points of
infinite length "through" the network?
In this case we may use Kolmogorov's
zero-one law to see that, for any given
p, the probability that an infinite cluster
exists is either zero or one. Since this
probability is increasing, there must be a
critical p (denoted by pc) below which
the probability is always 0 and above
which the probability is always 1. In

26
1386 ‫ زﻣﺴﺘﺎن‬- 38 ‫ﺷﻤﺎره‬
practice, this criticality is very easy to
observe. Even for n as small as 100, the
probability of an open path from the top
to the bottom increases sharply from
very close to zero to very close to one in
a short span of values of p.
In some cases pc may be calculated
explicitly. For example, for the square
lattice in two dimensions, pc = 1 / 2, a
fact which was an open question for
more than 20 years and was finally
resolved by Harry Kesten (11) in the
early '80s. More often than not, pc
cannot be calculated. For example, pc is
not known in three dimensions.
However, it turns out that calculating pc
is not necessarily the most interesting
thing to do. The universality principle
states that the value of pc is connected to
the local structure of the graph while the
behavior of clusters below, at and above
pc are invariants of the local structure,
and therefore, in some sense are more
natural quantities to consider.
This model is Bernoulli percolation. In
this model all bonds are independent.
This model is also called bond
percolation by physicists (12).
In chemistry and materials science,
percolation concerns the movement and
filtering of fluids through porous
materials. During the last three decades,
Percolation theory, an extensive
mathematical model of percolation, has
brought new understanding and
techniques to a broad range of topics in
physics, materials science as well as
geography. In mathematics, percolation
theory describes the behavior of
connected clusters in a random graph.
(10).
Hypothesis
In our model, we consider surrounding
environment of an assumed capillary
vessel as a porous media. The fixed
structures of this media act as
scaffolding and the other parts of it act
as pores within this scaffolding. To
move any cell within this media, they
must pass through this porous media to
reach their targets. Thus there must be
an open path from original location of a
cell and its target toward which it
migrates. The probability of existence
of an open path, according to
Percolation theory and the universality
principle, depends on the structure of
the porous media. If there are more
connections within this media, the pc is
low and the probability that an open
path exists is high. In contrast, if the
media gets more solid and has fewer
connections, the pc gets higher and the
probability of existence of an open path
gets lower. Thus, a cell can not reach its
target through this media easily. During
angiogenesis, EC at the tip of the new
sprout migrates through its surrounding
media, acts as a porous media. Thus, if
this porous media has a lot of
connections, the probability that an
open path for migration of EC exists is
high. Otherwise, EC can not reach its
target area easily through this solid
media.
Figure 2. Flow of fluid trough a porous media.
27

Discussion
Moving of cells within an environment
needs scaffolding up on which they can
migrate. The components of scaffolding
depend on its environment. For
example, in liver, ECM fibers act as
scaffolding up on which hepatocytes
migrate to renew themselves, after any
injury caused necrosis of hepatocytes
but has not altered lobular architecture.
If this scaffolding alters, hepatocytes
can not move regularly and they arise
regenerative nodules, like cirrhosis.
Arising of these nodules reflects the
altered reconstruction of lobular
architecture (13).
During angiogenesis, tip EC also needs
scaffolding that they can migrate
through its pores. For example, in
retina, neuron processes and glial cells
are fixed in their places. Thus, it seems
that they act as scaffolding in retinal
layer for migration of sprout tip during
angiogenesis. In normal condition, tip
EC, passes through the pores within that
scaffolding. Thus, retinal vasculature is
mimicry of structure of glial cells and
neuron processes. In diabetic
retinopathy, neuronal, glial and pericyte
damage might precede angiogenesis (6).
Thus, that porous media surrounding the
vessels changes and formation of new
vessel sprouts is not similar to the
primary vasculature.
Also, a circular avascular zone at the
fovea (6) indicates that this environment
is solid enough that does not allow
vessels to growth within it. Thus it can
be concluded that this media has very
high pc that the probability of the
existence of an open path toward the
center of the fovea is very low or even
zero.
In other conditions such as tumor
growth, in McDougall et al. (2006), the
probability of growth of the sprout tip in
three possible directions in a two-
28
Angiogenesis and Percolation theory
dimensional grid has been evaluated
(14). That two-dimensional grid has
been used for flow calculation from a
parent vessel toward a tumor.
Regardless the factors influence the
probability of growth of the sprout tip
through one connection of that grid; it
seems that if that grid has more
connections, the probability of arising
an open path between parent vessel and
tumor gets higher. Thus, by changing
that environment and making it more
solid which has fewer connections or
pores, one can make the probability of
existing an open path through which a
new sprout migrates, lower. Thus,
Percolation theory can be applied in this
condition too.
Conclusion
Local structure of surrounding media of
a cell influences migration routes of it,
like EC during angiogenesis. Thus, to
supply blood to a target area, one can
change the physical environment of a
capillary network to a suitable physical
one which allows new sprout tips to
growth toward a target area more
efficiently. Also, to inhibit
angiogenesis, by changing the physical
environment and making parent vessel’s
environment more solid (e.g., reducing
the pores within ECM) we might reach
our goals.
Acknowledgment
We gratefully acknowledge Nima
Lashkari for contributing references 9
through 12.
1386 ‫ زﻣﺴﺘﺎن‬- 38 ‫ﺷﻤﺎره‬

References 11- Kesten H. Percolation theory for

1- Kong HL, Crystal RG. Gene Therapy mathematicians. vol. 2. Birkhauser,
Strategies for Tumor Antiangiogenesis. Boston, Mass.. 1982.
J Natl Cancer Inst. 1998;90:273–86 12- Grimmett G. Percolation. 2nd
2- Pandya NM, Dhalla NS, Santani DD. Edition. Grundlehren der
Angiogenesis—a new target for future mathematischen Wissenschaften, vol
therapy. Vascular Pharmacology. 321, Springer, 1999.
2006;44:265–274. 13- Popper H, Zak FG. Pathologic
3- Fam NP, Verma S, Kutryk M, Aspects of Cirrhosis. American Journal
Stewart DJ. Clinician Guide to of Medicine. 1958;593-619.
Angiogenesis. circulation. 14- McDougall SR, Anderson ARA,
2003;108:2613-2618. Chaplain MAJ. Mathematical modelling
4- Persano L, Crescenzi M, Indraccolo of dynamic adaptive tumour-induced
S. Anti-angiogenic gene therapy of angiogenesis: Clinical implications and
cancer: Current status and future therapeutic targeting strategies. Journal
prospects. Molecular Aspects of of Theoretical Biology. 2006;241:564–
Medicine. 2007;28:87–114. 589.
5- Afzal, A., et al., Retinal and
choroidal microangiopathies:
Therapeutic opportunities, Microvasc.
Res. (2007),
doi:10.1016/j.mvr.2007.04.011
6- Gariano1 RF, Gardner TW. Retinal
angiogenesis in development and
disease. Nature. 2005;438:960-966.
7- Veale DJ, Fearon U. Inhibition of
angiogenic pathways in rheumatoid
arthritis: potential for therapeutic
targeting. Best Practice & Research
Clinical Rheumatology. 2006;20( 5):
941-947.
8- Moreno PR, Purushothaman KR,
Sirol M, Levy AP, Fuster V.
Neovascularization in Human
Atherosclerosis. Circulation.
2006;113:2245-2252.
9- Mazaheri AR, Zerai B, Ahmadi G,
Kadambi JR, Saylor BZ, Oliver M,
Bromhal GS, Smith DH. Computer
simulation of flow through a lattice
flow-cell model. Advances in Water
Resources. 2005;28:1267–1279.
10- Sahimi M. Applications of
percolation theory. 3rd edition. London;
Bristol, PA : Taylor & Francis, ©1994.

29