Trakia Journal of Sciences, Vol.1, No 1, pp 1-4, 2003
Copyright © 2003 Trakia University
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Review Article
RECENT INSIGHTS IN THE REGULATION OF ANGIOGENESIS AND
ITS ROLE IN HEALTH AND DISEASE
Andreas Bikfalvi*
Molecular Mechanisms of Angiogenesis Laboratory, (INSERM EMI 0113), University Bordeaux,
France
ABSTRACT
Angiogenesis (the formation of blood or lymphatic vessels) has become a focus of intense research.
Some of the key players such as Vascular Endothelial Growth Factors (VEGF) or angiopoetins have
been identified and several basic mechanisms have been discovered. Angiogenesis-based therapeutic
strategies for the treatment of cancer or other angiogenesis-related diseases also show promise. It is to
expect that a number of novel therapeutics come out of these studies. Thus, angiogenesis research is at
an exciting stage.
Key words: Angiogenesis, Cancer, Vasculogenesis
INTRODUCTION
Vascular development is governed by a
number of regulatory molecules called
« angiogenesis »
factors
(1-4).
These
molecules control vascular development either
positively (angiogenesis stimulators) or
negatively (angiogenesis inhibitors) (Figure
1).
In fact, in a number of settings, the
formation of a vascular network is the net
outcome of a critical balance between the
positive and the negative regulators. Factors
involved in vascular development may act at
the level of vasculogenesis or angiogenesis.
Vasculogenesis and angiogenesis are distinct
and are controlled by different regulatory
mechanisms (2) (Figure 2).. Vasculogenesis is
characterized by the differentiation of
endothelial progenitor cells and their
assembly. In opposite, angiogenic blood
vessels are formed from prexisiting one’s.
These two differents modes may imply
distinct
vasoformative
factors
and
mechanisms.
Vasculogenesis
and
angiogenesis both take place during
embryonic development and during the postnatal period. Furthermore, both processes are
occurring during pathological processes such
*Correspondence to: Andreas Bikfalvi, University
Bordeaux I, 33 405 Talence cedex, Phone: (33) 5 56 84
87 03, fax: (33) 5 56 84 87 05
E-mail: a.bikfalvi@croissance.u-bordeaux.fr
as cancer or after ischemia. It is, however, not
yet clear to what extent vasoformation, in the
adult, especially in pathological conditions, is
dependent on vasculogenesis. A recent study
suggests that a significant part of tumor blood
vessels is derived from endothelial progenitor
cells and therefore formed by vasculogenesis
(5). The respective participation of both
processes in vasoformation is probably
context-dependent and may depend on the
pathology or the tumor type.
Researchers in the field have divided the
vasoformative process into different steps
which include proliferation, migration,
sprouting,
tubulogenesis,
branching,
remodelling (pruning), and vessel maturation.
Besides these, intussusception and septation
have also been reported to contribute to
vasoformation through angiogenesis. For
these latter two, tissue pillars are integrated
into existing blood vessels, which then give
rise to new vascular tubes. Regulatory
molecules controlling these different steps
have been identified such as Vascular
Endothelial Growth factors (VEGFs),
fibroblast
growth
factor
(FGFs),
angiopoietins, Tie1 or Tie2 receptor kinase (14, 6).
The elucidation of mechanisms of action of
these factors and receptors is now the focus of
intense research. How these different factors
and signals are integrated, remains to be
addressed.
1
A. BIKFALVI
Figure 1. The angiogenic balance. Angiogenesis is controlled by positive and negative regulators. The net outcome of the
effect on angiogenesis is due to the respective concentrations/activities of that act on the vasculature. These regulators
are modulated by hypoxia, oncogenes or growth factors which all either increase the positive regulators, decrease the
negative regulators or do both.
Figure 2. Paracrine relationships in angiogenesis. An embryonic or adult healthy or pathological tissue (i.e; tumor)
produces higher relative amounts of positive regulators than negative regulators to stimulate vascular development. This
will either induce the formation of vascular tubes by sprouting (angiogenesis) or by recruitment of endothelial cell
progenitors (EPC) that differentiate in situ into vascular endothelial cells and incorporate into vascular tubes
(vasculogenesis). Hematopoietic cells (HC) from the bone marrow are also recruited to reinforce this effect.
Another recent development in the
angiogenesis field is the relationship of
angiogenesis and neurogenesis (2). Vascular
and neural development share similarities and
are regulated by survival and differentiation
factors. It has been recently recognized that
neuropillin-1 (NRP-1) and neuropillin-2
(NRP-2) that are receptors for the
semaphorins/collapsins are also coreceptors
for
VEGF
family
members
(2,7).
2
Furthermore, Ephrins and their respective Eph
receptors that provide guidance cues for
axons,
also
regulate
arterio-venous
differentiation and vessel assembly (2,8).
Lymphatic vessels seems two require, to
some extent, their own set of regulators and
mechanisms.
Lymphangiogenesis
is
controlled by the prox gene, VEGF-C, VEGFD, VEGF receptor-3 (VEGFR3) and fibroblast
growth factors but not by VEGF-A or VEGF-
Trakia Journal of Sciences, Vol.1, No 1, 2003
A. BIKFALVI
B (2, 9-10). It has been recently demonstrated
that metastatic spread in transgenic mice can
be induced by VEGF-C expression (10). Are
vasculogenesis and angiogenesis also basic
principles for the formation of lymphatic
blood vessels ? It is possible that lymphatic
endothelial cell precursors exist, similar to
the endothelial cell precursors described for
blood vessels, that participate to lymphatic
vasculogenesis (11).
Another issue of angiogenesis factors is the
question of their specificity. It has been
believed over the past 10 years that the master
regulators of vasoformation are specific for
the vasculature. This is perhaps less true as
initially thought. As an example, VEGFs
have been claimed to regulate specifically the
vascular development but not to interact with
other cell types or tissues. This claim was
mainly supported by gene knock-out studies
in mice of VEGF-A or its tyrosine kinasereceptors, in which significant vascular
phenotypes were revealed (12). However,
recent evidence indicate that VEGFs are
important for other functions as well such as
neural stem cell survival or hematopoiesis
(13,14). Thus, VEGFs are becoming broad
range-morphogens and may resemble in this
respect FGF family members.
A large panel of endogenous regulatory
molecules, fragments or designer drugs are
under pre-clinical or clinical evaluation for
angiogenesis or antiangiogenesis therapy (1,2,
15). Among these, VEGF kinases inhibitors
are very promising agents. It is, however,
important, especially for anti-angiogenesis
strategies, to optimise these therapies. An
interesting approach for the optimisation of
antiangiogenesis therapy is certainly its
association with low dose-chemotherapy
(15,16,17). Another approach is the
combination of several anti-angiogenesis
drugs. For example, the association of
endostatin, angiostatin and TNP470 is more
effective than single drugs alone (18).
However, these combinations should be
designed rationally and molecules with
complementary mechanisms of actions should
be
associated.
For
example,
lymphangiogenesis inhibitors may be
associated with blood vessel inhibitors as this
combination would inhibit the primary tumor
and the metastatic spread through the
lymphatics. The development of more specific
lymphangiogenesis inhibitors such as
indolinones, that inhibit the interaction of
VEGF-C and D with VEGFR3, is, in this
respect, important (19). An interesting venue
for further developments is also the
identification and optimisation of molecules
already in clinical use such as HIV protease
inhibitors that are potent antiangiogenesis
molecules and promote the regression of
Kaposi sarcoma lesions (20).
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Trakia Journal of Sciences, Vol.1, No 1, 2003