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LeadDiscovery Reports
Arteriogenesis as a treatment of stroke
Angiogenesis represents
an emerging therapeutic target which by 2006, is expected to command a
market of $1.75 billion. A growing component of this market centers on
the use of stimulators of angiogenesis for the treatment of ischemic
diseases. Considerable evidence supports the use of the prototypic
angiogenic growth factor, VEGF for the treatment of various related
conditions including angina, myocardial infarction and peripheral artery
occlusive disease (PAOD). Together, preventing the occurrence and
reoccurrence of these conditions remain a pressing clinical priority.
Well over 12.5 million people in the US suffer from one or more ischemic
condition resulting in around 1 million deaths each year and an annual
health care expenditure of over $US100 billion. A number of clinical
studies have demonstrated that VEGF gene therapy can be beneficial in
patients with myocardial disease or PAOD.
About 600,000 Americans suffer ischemic stroke each year, 8% of whom die
within 30 days. A further 15-30% are permanently disabled and 20%
require institutional care. Direct and indirect costs of stroke is
therefore immense. The treatment of ischemic stroke remains one of the
most challenging areas of medicine today and since many patients present
far beyond the three hour window of current treatments, not surprisingly
most patients receive only palliative care. In order to open the window
of therapeutic opportunity the pharmaceutical industry is currently
focusing on the development of molecules able to increase
vascularization in the brain following ischemic stroke. Although several
reports have documented the therapeutic stimulation of angiogenesis in
the brain, these studies failed to demonstrate improvement of stroke
outcome. This is not surprising, because angiogenesis is too slow to
compensate for the sudden decline of flow after acute vascular
occlusion.
In contrast to angiogenesis which involves the de novo development of
blood vessels, arteriogenesis represents the adaptive proliferation of
preexisting collateral pathways. This represents an effective biological
rescue system, limiting the detrimental effects of arterial stenosis.
German researchers have recently demonstrated that occlusion of the left
carotid artery and both vertebral arteries induced a significant
redistribution of blood flow via the left posterior cerebral artery,
which increased its diameter 2-fold. This was independent of expression
of the angiogenic factor VEGF. This adaptive arteriogenesis led to a
significant improvement of the hemodynamic capacity of the hypoperfused
brain. Certain CC chemokines (monocyte chemotactic protein-1),
fibroblast growth factors, or granulocyte-macrophage colony-stimulating
factor (GM-CSF) has been shown to increase collateral conductance.
Furthermore, a recent clinical trial demonstrated a positive effect of
GM-CSF on therapeutically enhanced arteriogenesis in a small cohort of
patients with coronary artery disease.
Most recently Ivo Buschmann from Albert Ludwigs University and
colleagues have demonstrated for the first time that it is possible to
pharmacologically increase the rate of arteriogenesis in the brain.
Using a nonlethal model this group demonstrated that brain hypoperfusion
increased the diameter of the left posterior cerebral artery over a
three week period. This effect was enhanced by the application of GM-CSF
such that the diameter observed at three weeks was observed after only
one week in treated animals. GM-CSF treatment resulted in significant
functional effects since in control animals brain hypoperfusion reduced
the hemodynamic reserve of the brain, while in GM-CSF treated animals
this functional decline was reversed.
This study is important because although the spontaneous proliferation
of collateral represents an endogenous protective mechanism to ischemia
its time-course is too slow to fully prevent the detrimental effects of
vascular occlusion. The observation that GM-CSF can dramatically
potentiate this response suggests that this mediator, its mimics, or
other stimulants of arteriogenesis may be of use in the treatment of
stroke. Stimulating arteriogenesis should be viewed as being distinct
from that of angiogenesis. While the protective angiogenesis usually
occurs in the penumbra of stroke victims and may represent an effort to
maintain tissue viability in the affected region, arteriogenesis is a
more proximal and spatially separated process that serves to counter
reduced flow through occluded arteries. This suggests that stimulating
arteriogenesis may offer an additional rather than an alternative
approach to angiogenesis.
Entry date Friday, September 19, 2003
Adapted from Buschmann et al, Circulation. 2003 Aug 5;108(5):610-5. Epub
2003 Jun 30
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