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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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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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Angiogenesis and Newton′s law

Figure 1. Intra and extra vascular forces act on vascular wall

Newtonian’s first law stated as: “Every outward and extra vascular factors
body perseveres in its state of being at include forces that act on opposite
rest or of moving uniformly straight direction of intravascular forces. The
forward, except insofar as it is intravascular forces are caused by blood
compelled to change its state by force pressure within capillary lumen and the
impressed.” (8). This law is also called extra vascular forces are caused by
the law of inertia. Newton arranged his basement membrane and ECM
laws in hierarchical order for good components and cells that are around
reason (for more details, see reference capillary wall. Thus, when forces are in
9). balance, capillary wall does not move
The net force on an object is the vector but if forces from inside increase and
sum of all the forces acting on the forces from outside decrease, capillary
object. Newton's first law says that if wall protrudes, Figure 1.
this sum is zero, the state of motion of
the object does not change. Essentially, Discussion
it makes the following point: an object Most of investigations analyze
that is not moving will not move until a angiogenesis process by regarding that
net force acts upon it. some signals, in the form of growth
The law serves to emphasize the factors, from out of vessels act on ECs
elementary causes of changes in an to activate them and make them digest
object's state of motion: forces. their extracellular matrix (ECM) by
some enzymes, especially matrix
Hypothesis metalloproteinase (MMP), and migrate
In our model, intravascular factors toward higher concentration of growth
include forces which push capillary wall factors. It is proposed that a balance

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between pro-angiogenic and anti- As shown in figure 1, angiogenesis is


angiogenic factors control angiogenesis. initiated by protruding capillary wall
Thus it is controlled through a series of outward and forming a new sprout.
“on” and “off” regulatory switches: the Thus, intravascular forces must be in
main “on switches” are known as pro- excess of extra vascular forces. When
angiogenic growth factors; the main capillary blood pressure increases,
“off switches” are known as anti- forces act on capillary wall from inside
angiogenic factors. When pro- increase. Increasing capillary blood
angiogenic growth factors are produced pressure may be caused by local
in excess of anti-angiogenic factors, the vasodilation in some situations in which
balance favors new sprout formation. demand of a part of the body gets more
When inhibitors are present in excess of than its blood supply, like tissue
stimulators, angiogenesis is stopped (1). ischemia and tumor growth. As
To interfere therapeutically with this mentioned above forces from outside
process and control it, too many are caused by supporting structures of
attempts have been done to identify capillary wall. Thus, if these supporting
some pro-angiogenic and anti- structures get destroyed or get away
angiogenic factors, listed in table 2. from capillary wall, these forces
Thus, to inhibit angiogenesis, some decrease. For example, in retina,
growth factors or MMPs have been neurons and glial cells act as supporting
targeted to be blocked and to stimulate structures for retinal blood vessels. As a
this process, some of these growth complication of diabetes mellitus,
factors have been administered to act on neurons may be destroyed (5). Thus
ECs and also some clinical trials have supporting structures of vessels in retina
been made to exploit some growth get destroyed. Then, imbalance among
factors therapeutically, especially forces, act on capillary wall from
vascular endothelial growth factor outside and inside, causes wall to be
(VEGF) and fibroblast growth factor protruded. Thus micro aneurysms and
(FGF) (2,4,10) but some of them have then, new sprouts form.
been disappointing, probably owing to It is clear that if difference between
unresolved questions regarding optimal forces act from inside and outside gets
dose, optimal timing, treatment very high and then, net forces that
strategies such as protein delivery or its protrude capillary wall gets more than
gene delivery (11) and type of growth maximal wall tension which it can
factor and combinations of them and tolerate, capillary wall ruptures and
route of delivery, long-term safety bleeding occurs.
(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.

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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 References
Thus, by controlling physical forces 1- Pandya NM, Dhalla NS, Santani DD.
apply on capillary wall, we can Angiogenesis—a new target for future
stimulate new sprout formation or therapy. Vascular Pharmacology.
inhibit it. In order to stimulate new 2006;44:265–274.
sprout formation, these physical forces 2- Fam NP, Verma S, Kutryk M,
must be high enough to protrude Stewart DJ. Clinician Guide to
capillary wall and low enough to Angiogenesis. circulation.
prevent from its rupture and to inhibit 2003;108:2613-2618.
new sprout formation, physical forces 3- Persano L, Crescenzi M, Indraccolo
from outside must be high enough to S. Anti-angiogenic gene therapy of
prevent capillary wall protrusion. cancer: Current status and future
prospects. Molecular Aspects of
Acknowledgment Medicine 28 (2007) 87–114.
We gratefully acknowledge Dr. 4- Afzal, A., et al., Retinal and
Mahmood Shabestari. choroidal microangiopathies:
Therapeutic opportunities, Microvasc.
Res. (2007), doi:10.1016/j.mvr. 2007.
04. 011

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5- Gariano1 RF, Gardner TW. Retinal Applications in Cardiovascular


angiogenesis in development and Medicine. J Am Coll Cardiol.
disease. Nature. 2005:438;960-966. 2007;49:1015–26.
6- Veale DJ, Fearon U. Inhibition of 15- Tse HF, Lau CP. Therapeutic
angiogenic pathways in rheumatoid Angiogenesis With Bone Marrow—
arthritis: potential for therapeutic Derived Stem Cells. Journal of
targeting. Best Practice & Research Cardiovascular Pharmacology and
Clinical Rheumatology. 2006:20( 5); Therapeutics. 2007;12(2):89-97.
941-947.
7- Moreno PR, Purushothaman KR,
Sirol M, Levy AP, Fuster V.
Neovascularization in Human
Atherosclerosis. Circulation.
2006;113:2245-2252.
8- Isaac Newton, The Principia, A new
translation by I.B. Cohen and A.
Whitman, University of California
press, Berkeley 1999
9- Galili, I, Tseitlin, M. Newton's first
law: text, translations, interpretations,
and physics education. Science and
Education. 2003;12 (1):45-73.
10- Emanueli1 C, Madeddu P.
Changing the logic of therapeutic
angiogenesis for ischemic disease.
TRENDS in Molecular Medicine.
2005;11(5):207-216.
11- Nordlie MA, Wold LE, Simkhovich
BZ, Sesti C, Kloner RA. Molecular
Aspects of Ischemic Heart Disease:
Ischemia/Reperfusion-Induced Genetic
Changes and Potential Applications of
Gene and RNA Interference Therapy. J
Cardiovasc PharmacolTherapeut.
2006;11(I): 17-30.
12- Molin D, Post MJ. Therapeutic
angiogenesis in the heart: protect and
serve. Current Opinion in
Pharmacology. 2007;7:158–163.
13- Freedman SB, Isner JM.
Therapeutic Angiogenesis for Coronary
Artery Disease. Ann Intern Med.
2002;136:54-71.
14- Ylä-Herttuala S, Rissanen TT,
Vajanto I, Hartikainen J. Vascular
Endothelial Growth Factors Biology
and Current Status of Clinical

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