| There
have been a number of recent scientific publications
either theorising that it should be possible to
reduce the impact of endometriosis by inhibiting
the growth of new blood vessels supporting the endometriotic
lesion, or presenting data from animal models showing
that angiogenesis inhibitors can inhibit the growth
of endometriotic explants. To further explore the
potential utility of angiogenesis inhibitors in
treating endometriosis, it is important to have
some understanding of the complexities of angiogenesis
as a biological process.
Angiogenesis is
defined as the process whereby new blood vessels
are formed from pre-existing vessels. Depending
on their metabolic activity, any cluster of cells
greater than approximately 1mm3 cannot receive sufficient
oxygen or nutrients by diffusion alone, and hence
requires supply by functioning blood vessels. There
are at least 4 different mechanisms by which angiogenesis
can occur: sprouting, intussusception, elongation/widening,
and incorporation of circulating endothelial cells
into vessels (Folkman and D’Amore, 1996, Risau,
1997, Asahara et al, 1999, Burri and Djonov,
2002). Each mechanism involves a different series
of steps that can include activation of endothelial
cells, breakdown of the basement membrane, migration
and proliferation of endothelial cells, tube formation,
and stabilisation of the tube with the formation
of new basement membrane and coverage of the vessel
wall with pericytes and vascular smooth muscle cells.
To add to the complexity
of multiple mechanisms and steps of angiogenesis,
numerous factors have been identified as playing
direct or indirect roles in regulating each part
of the angiogenic process. In human endometrium,
where the angiogenic mechanisms are potentially
similar to those in endometriotic lesions, blood
vessels grow and regress every menstrual cycle under
the overall control of oestrogen and progesterone.
However, regulation of endometrial angiogenesis
is not simple, with evidence now emerging that oestrogen
can both promote and inhibit endometrial vessel
growth under different circumstances (Girling and
Rogers, 2005). In addition, a large number of angiogenic
factors and inhibitors have been identified in human
endometrium, although the precise role they play
in regulating angiogenesis during the menstrual
cycle and pregnancy remains to be elucidated
The many regulatory
factors and steps contributing to each angiogenic
mechanism provide a large number of different targets
for disruption or inhibition. As a consequence,
many naturally occurring and synthetic compounds
with anti-angiogenic activity have now been identified.
While all of these have demonstrable anti-angiogenic
activity in in vitro or defined in vivo models,
it is a common observation that their ability to
completely block angiogenesis in vivo is often restricted.
An explanation for this observation may be that
since angiogenesis is such a fundamental process
for survival of the organism, alternative pathways
rapidly come in to play if one step is blocked.
Examples of alternative pathways, or redundancy,
can be found in other biological processes that
are fundamental to evolutionary survival.
In assessing the
potential of anti-angiogenic therapy as a treatment
for endometriosis, it is relevant to consider 2
major issues: the likely effectiveness of the treatment,
and the risk of unwanted side effects.
The potential effectiveness
of anti-angiogenic therapy for treating endometriosis
can only be assessed based on limited animal studies,
since to date there have not been any reported clinical
trials in humans. One of the initial animal studies
used human endometrial tissues transplanted to immuno-compromised
nude mice, and inhibited angiogenesis through limiting
availability of vascular endothelial growth factor
(VEGF) by using either a truncated soluble receptor,
or a purified VEGF antibody (Hull et al,
2003). Both reagents significantly inhibited endometrial
explant growth within the mice, with pericyte-free
vessels being significantly reduced. The same authors
also reported that a large number of blood vessels
supplying endometrotic lesions in women are devoid
of pericytes, and hence in theory should also be
vulnerable to disruption by anti-angiogenic agents.
A second study, using a similar human endometrial
tissue into nude mouse transplantation model, investigated
4 different anti-angiogenic agents, administered
3 weeks after the endometrial explants had been
transplanted (Nap et al, 2004). All 4 inhibitors
were able to reduce established explants, with the
pericyte free vessels again being targeted. This
study also reported that angiogenesis associated
with other events such as wound healing and uterine
growth were unaffected by the treatments, although
this was not investigated in great detail. An alternative
experimental model uses endometrium surgically removed
from and transplanted back into the same animal.
In hamsters, growth of such autologous endometrium
transplanted into a dorsal skinfold chamber can
be more effectively blocked by compounds that inhibit
a number of angiogenesis factors simultaneously
(VEGF, fibroblast growth factor and platelet derived
growth factor), rather than VEGF alone (Laschke
et al, 2006).
There is always
a concern with anti-angiogenic therapy that blood
vessel growth necessary for normal function may
be blocked. In a model using mouse endometrium transplanted
into mouse peritoneal cavity, Dabrosin et al
(2002) reported that overexpression of the
angiogenic inhibitor angiostatin by adenoviral transfection
eradicated established endometrial explants, but
also impaired ovarian function, decreased uterine
weight and increased body weight. Significant angiogenesis
occurs in the female reproductive tract during the
ovulatory cycle, with the ovarian follicle, the
corpus luteum and the uterine endometrium all exhibiting
active angiogenesis. Unwanted inhibition of angiogenesis
in these organs would be a significant problem.
In other studies where side effects of anti-angiogenic
therapy were monitored, it has been reported that
endostatin, and a short peptide derived from endostatin,
are able to inhibit endometrial transplants in mice
by approximately 50% without affecting angiogenesis
in other organs (Becker et al, 2005, 2006).
These experiments
raise a number of issues. All rely on transplantation
of existing normal endometrium into the peritoneal
cavity, rather than spontaneous growth of endometriotic
lesions as occurs in humans. It is unclear whether
the specific angiogenic mechanisms being studied
in the endometrial transplant animal models are
the same as those that occur in the different spontaneous
types and stages of human endometriotic lesions.
The animal experiments are all short-term, while
endometriosis is a chronic disease where treatment
may need to be given over years. Thus, by the time
symptoms occur and a diagnosis is reached in humans,
the most suitable time for angiogenesis inhibitor
treatment may be well past. Finally, and of greatest
concern, is the risk of giving angiogenesis inhibitors
to women who may be pregnant. Angiogenesis is an
essential component of normal growth and development
of the foetus, and any inhibition of normal vessel
growth can have dire consequences for the unborn
child, as experience with thalidomide tragically
demonstrated.
So where to from
here? Clearly, more basic knowledge is required
about both the pathophysiology of endometriosis,
and the mechanisms of angiogenesis and how to inhibit
them. It is possible that endometriosis-specific
angiogenic mechanisms could be identified and safely
targeted, thus allowing long-term treatment without
risk of unwanted side effects. Alternatively, very
specific short-term treatment regimens could be
devised to reduce endometriotic burden prior to
specific events such as surgery. Realistically,
and regardless of the science, it is questionable
in the modern litigious age whether in the light
of past history any company would be prepared to
take the risk of marketing anti-angiogenic pharmaceuticals
to women who might become pregnant while using them.
REFERENCES
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PA. Blood Vessel Formation: What is Its Molecular
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2. Risau W. Mechanisms of Angiogenesis. Nature 1997;386:671-4
3. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore
C, Silver M, Kearne M, Magner M & Isner JM.
Bone marrow origin of endothelial progenitor cells
responsible for postnatal vasculogenesis in physiological
and pathological neovascularization. Circ Res 1999;85:221-28.
4. Burri PH, Djonov V. Intussusceptive angiogenesis
– the alternative to capillary sprouting.
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10. Becker CM, Sampson DA, Rupnick MD, Rohan RM,
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K, Folkman J & D’Amato RJ. Short synthetic
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