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