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LeadDiscovery Reports
Mutual regulation of angiogenesis and adipogenesis
Angiogenesis, the
formation of new blood vessels, is crucial to a number of physiological
processes as well as in disease states. Consequently angiogenesis
represents an emerging therapeutic target which by 2006, is expected to
command a market of $1.75 billion. Tumor vascularization is key to the
development of solid tumors and the vast majority of pharmaceutical
activity surrounding angiogenesis relates to the development of
therapeutic strategies to destroy existing tumor vasculature or to
prevent neovascularization. Despite early enthusiasm for angiogenesis
inhibitors as safe and effective anticancer drugs, several Phase III and
Phase II trials have proved disappointing. Newer strategies are however
being developed which will hopefully confer greater efficacy to this
field (for an analysis of pharmaceutical activity surrounding the
development of angiogenesis inhibitors
click here).
New indications for inhibitors of angiogenesis include rheumatoid
arthritis and this approach is highlighted both in the “Focus on
Immunology, Inflammation & Infectious Disease” section of this edition
of TherapeuticAdvances (click here) and in greater detail in our recent
dossier “Rheumatoid arthritis: Emerging drug discovery targets and
therapeutic candidates” (click here). In their 2002 paper Judah Folkman’s group reported that angiogenesis inhibitors were able to
induce weight loss without altering calorific intake, a finding which
has led to obesity emerging as a further indication for inhibitors of
angiogenesis. This is of particular interest since obese individuals
have a considerably increased risk of developing cancer and molecules
that limit obesity by blocking angiogenesis may also prevent the
development of tumors in these patients.
The identification of new targets for obesity therapeutics represents a
key priority for the pharmaceutical industry. This has been driven by
the large and growing numbers of obese individuals around the world, the
high incidence of serious co-morbidities, and a market predicted to
reach $3.7 billion by 2008. Obesity occurs when calorific intake exceeds
energy expenditure. LeadDiscovery has recently analyzed two emerging
anti-obesity targets, ghrelin which regulates food intake (click here
for more), and the retinoids which also plays a role in both food intake
as well as energy expenditure (click here for more).
In their recent Circulation Research article, Fukumura et al employed a
model in which preadipocytes were implanted into a mouse dorsal skin
chamber in order to facilitate a simultaneous and longitudinal study of
angiogenesis and adipogenesis. The implantation of preadipocytes was
followed by an increase in angiogenesis that led to the development of a
dense capillary network. This occurred at the same time as the
differentiation of preadipocytes into adipocytes. The activation of
PPARgamma is considered an absolute requirement for the process of
adipocyte differentiation and blocking this process not only prevented
adipogenesis but it also limited angiogenesis and subsequent maturation
of the neo-vasculature. This suggests that pre-adipocyte differentiation
regulates the accompanying vascularization process. On the other hand
blocking the VEGF receptor, VEGFR-2, prevented angiogenesis and also
preadipocyte differentiation. The latter was not a direct effect but was
suggested to result from the release of mediators from endothelial cells
in response to VEGF. The data from the present study are particularly
exciting since they demonstrated that angiogenesis and adipogenesis are
dependent on one another and confirm that blocking angiogenesis may be
an approach to obesity. On the basis of the present data VEGFR-2
antagonists deserve clinical evaluation in the context of obesity.
Neovascularization is required for tissue repair and since most tissue
have adipocytes interspersed within their matrix it may be that
adipocytes are an important component of the response to damage due to
their ability to regulate neovascularization. The therapeutic activity
of molecules able to stimulate adipocyte differentiation at sites of
injury thus represents a novel area of research. This may be
particularly important following, for example, ischemic damage in the
central nervous system or the heart following stroke and myocardial
infarction. Conversely it would be interesting to determine the effect
of blocking adipocyte differentiation on tumor vasularization.
Entry
date Wednesday, November 12, 2003
Adapted from Fukumura et al, Circ Res. 2003 Oct 31;93(9):e88-97
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