Angiogenesis and Newton′s law

Newton′s law in
angiogenesis

Nourozpour A, Mehdizadeh AR, Fazelzadeh A

Sadra–Sina Interdisciplinary Research Group
Mashad University of Medical Sciences

Abstract

Angiogenesis begins with protrusion of By considering these forces and

capillary wall and formation of new controlling them, we could more
sprouts from pre-existing blood vessels. efficiently handle this process in
Broadly accepted today, this process is pathologic conditions.
initiated by releasing some growth Keywords: Angiogenesis, growth
factors from a demand area to act on factors, sprout, Newton's law,
endothelial cells of pre-existing vessels mechanical force.
and make them activated and migrated
through growth factor gradient. By this
viewpoint, many investigations have
been done but the real cause of it has
not been clearly understood. By
reviewing this process, we could look at
it through a different point.
We hypothesize that mechanical forces
act on capillary wall from inside and
outside of vessel, may be initiating
factor of angiogenesis.

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1386 ‫ زﻣﺴﺘﺎن‬- 38 ‫ﺷﻤﺎره‬

Introduction
Angiogenesis refers to sprouting of new Table 1. Some pathologic conditions in
which angiogenesis may be involved
vessels from preexisting blood vessels
(1). Some investigations demonstrate
that this process must be involved in Conditions in which angiogenesis
some pathologic conditions, must get stimulated.
summarized in table 1.To stimulate
angiogenesis, some intra and extra Myocardial ischemia2
vascular factors may affect on Peripheral ischemia1
endothelial cells (EC). Most of the Wound healing1
investigations analyze this process by
regarding that some signals, in the form
of growth factors, from out of vessels Conditions in which angiogenesis
act on ECs to activate them and make must get inhibited.
them digest their extracellular matrix
(ECM) by some enzymes, especially Tumor growth3
matrix metalloproteinase (MMP), and Diabetic retinopathy4,5
migrate toward higher concentration of Retinopathy of prematurity5
growth factors, Figure 1. Rheumatoid arthritis6
In order to stimulate it, some Atherosclerotic plaques7
investigations have been done by
get disturbed. It means that if these
increasing concentration of growth
factors are in balance, capillary wall
factors in target tissue. Also, to inhibit
would not get protruded but if
it, some growth factors or MMPs have
intravascular factors stimulate capillary
been targeted to be blocked. To control
wall to be protruded and extra vascular
this process, we should look at it again
factors facilitate its protrusion, capillary
and consider all factors that may
wall get ready to form a new sprout. It
influence on sprout formation.
is reminiscent of Newton’s first law, as
How a new sprout forms? At the
discussed below.
beginning of angiogenesis, in order to
Newton's laws of motion: Newton's
new sprout formation, capillary wall
laws of motion are three physical laws
must be protruded outward.
which provide relationships between the
In most of investigations, it has been
forces acting on a body and the motion
proposed that the cause of this
of the body, first compiled by Sir Isaac
protrusion is some growth factors that
Newton. Newton's laws were first
act on ECs. Then ECs get activated and
published together in his work
digest its basement membrane by some
Philosophiae Naturalis Principia
enzymes and then, protrude, figure 1.
Mathematica (1687). The laws form the
By considering intra and extra vascular
basis for classical mechanics. Newton
factors together, we can conclude that
used them to explain many results
angiogenesis occurs when the balance
concerning the motion of physical
between intra and extra vascular factors
objects (8).

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Figure 1. Intra and extra vascular forces act on vascular wall
Newtonian’s first law stated as: “Every
body perseveres in its state of being at
rest or of moving uniformly straight
forward, except insofar as it is
compelled to change its state by force
impressed.” (8). This law is also called
the law of inertia. Newton arranged his
laws in hierarchical order for good
reason (for more details, see reference
9).
The net force on an object is the vector
sum of all the forces acting on the
object. Newton's first law says that if
this sum is zero, the state of motion of
the object does not change. Essentially,
it makes the following point: an object
that is not moving will not move until a
net force acts upon it.
The law serves to emphasize the
elementary causes of changes in an
object's state of motion: forces.
Hypothesis
In our model, intravascular factors
include forces which push capillary wall
20
Angiogenesis and Newton′s law
outward and extra vascular factors
include forces that act on opposite
direction of intravascular forces. The
intravascular forces are caused by blood
pressure within capillary lumen and the
extra vascular forces are caused by
basement membrane and ECM
components and cells that are around
capillary wall. Thus, when forces are in
balance, capillary wall does not move
but if forces from inside increase and
forces from outside decrease, capillary
wall protrudes, Figure 1.
Discussion
Most of investigations analyze
angiogenesis process by regarding that
some signals, in the form of growth
factors, from out of vessels act on ECs
to activate them and make them digest
their extracellular matrix (ECM) by
some enzymes, especially matrix
metalloproteinase (MMP), and migrate
toward higher concentration of growth
factors. It is proposed that a balance
1386 ‫ زﻣﺴﺘﺎن‬- 38 ‫ﺷﻤﺎره‬
between pro-angiogenic and anti-
angiogenic factors control angiogenesis.
Thus it is controlled through a series of
“on” and “off” regulatory switches: the
main “on switches” are known as pro-
angiogenic growth factors; the main
“off switches” are known as anti-
angiogenic factors. When pro-
angiogenic growth factors are produced
in excess of anti-angiogenic factors, the
balance favors new sprout formation.
When inhibitors are present in excess of
stimulators, angiogenesis is stopped (1).
To interfere therapeutically with this
process and control it, too many
attempts have been done to identify
some pro-angiogenic and anti-
angiogenic factors, listed in table 2.
Thus, to inhibit angiogenesis, some
growth factors or MMPs have been
targeted to be blocked and to stimulate
this process, some of these growth
factors have been administered to act on
ECs and also some clinical trials have
been made to exploit some growth
factors therapeutically, especially
vascular endothelial growth factor
(VEGF) and fibroblast growth factor
(FGF) (2,4,10) but some of them have
been disappointing, probably owing to
unresolved questions regarding optimal
dose, optimal timing, treatment
strategies such as protein delivery or its
gene delivery (11) and type of growth
factor and combinations of them and
route of delivery, long-term safety
(2,10,12,13,14) Recently, stem cell
therapy especially bone-marrow derived
stem cells, to stimulate angiogenesis in
some diseases like ischemic heart
disease (IHD) has been done (15), but
those previous questions remained to be
solved for growth factor therapy, also
remain for this method of treatment. It
seems that it might be needed to be
reconsidered.
As shown in figure 1, angiogenesis is
initiated by protruding capillary wall
outward and forming a new sprout.
Thus, intravascular forces must be in
excess of extra vascular forces. When
capillary blood pressure increases,
forces act on capillary wall from inside
increase. Increasing capillary blood
pressure may be caused by local
vasodilation in some situations in which
demand of a part of the body gets more
than its blood supply, like tissue
ischemia and tumor growth. As
mentioned above forces from outside
are caused by supporting structures of
capillary wall. Thus, if these supporting
structures get destroyed or get away
from capillary wall, these forces
decrease. For example, in retina,
neurons and glial cells act as supporting
structures for retinal blood vessels. As a
complication of diabetes mellitus,
neurons may be destroyed (5). Thus
supporting structures of vessels in retina
get destroyed. Then, imbalance among
forces, act on capillary wall from
outside and inside, causes wall to be
protruded. Thus micro aneurysms and
then, new sprouts form.
It is clear that if difference between
forces act from inside and outside gets
very high and then, net forces that
protrude capillary wall gets more than
maximal wall tension which it can
tolerate, capillary wall ruptures and
bleeding occurs.
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 Angiogenesis and Newton′s law

Table 2. Some pro–angiogecin and anti–angiogenic factors.

Pro-angiogenic Anti-angiogenic

VEGF Angiostatin
Angiopoietin-1 Anti-angiogenic anti-thrombin III
β-Estradiol Canstatin
FGF Endostatin (collagen XIII fragment)
IL-8 Fibronectin fragment
Leptin Heparinases
MCP-1 IFN-α,β,χ
MMPs IL4, IL12, IL18
NOS Plasminogen activator inhibitor
PDGF-BB PEDF
TNF-α Prolactin 16 kDa fragment
Angiogenin TSP-1
TGF Retinoids

(Abbreviations: VEGF—vascular endothelial growth factor; FGF—fibroblast growth factor; IL8—

interleukin 8; MCP-1—macrophage chemoattractant protein; MMPs—matrix metalloproteases;
NOS—nitric oxide synthase; PDGF-BB—platelet derived growth factor-BB; TGF—transforming
growth factor; TNF—tumor necrosis factor; IFN-α,β,χ—interferon-α,β,χ; PEDF—pigment
epithelium derived growth factor; TSP-1—thrombospondin-1).

Conclusion
Thus, by controlling physical forces
apply on capillary wall, we can
stimulate new sprout formation or
inhibit it. In order to stimulate new
sprout formation, these physical forces
must be high enough to protrude
capillary wall and low enough to
prevent from its rupture and to inhibit
new sprout formation, physical forces
from outside must be high enough to
prevent capillary wall protrusion.
Acknowledgment
We gratefully acknowledge
Mahmood Shabestari.
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