Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor.
BACKGROUND
Colony-stimulating factors (CSFs) have been shown to effectively induce arteriogenesis in the hindlimb. Moreover, clinical trials demonstrated positive effects of CSFs on arteriogenesis in patients with coronary artery disease. However, patients with cerebrovascular disease have not yet profited from treatments aimed at the growth of brain vessels. Thus far, angiogenesis studies have failed to demonstrate improvement of stroke outcome. Arteriogenesis differs from angiogenesis in that it substitutes arterial collaterals for the occluded artery.


RESULTS
We tested in a novel brain arteriogenesis rat model (occlusion of vertebral plus left carotid artery [3-VO]) the application of CSFs or saline over 7 or 21 days. On 3-VO postmortem, latex perfusion demonstrated a time- and treatment-dependent arteriogenesis of the posterior cerebral artery (PCA). In saline-treated animals, the PCA diameter increased by 39%; in granulocyte-macrophage (GM)-CSF-treated animals, this increase was significantly faster (72% after 1 week). Functionally, saline-treated animals exhibited a decline of CO2 reactivity (mm Hg) from 1.48% to 0.1% compared with GM-CSF-treated animals (1.43% arterial pCo2 change after 1 week). This difference remained significant after 3 weeks. This functional improvement correlated with increased numbers of CD68-positive macrophages in histological sections of the PCA in GM-CSF--treated animals and only a few macrophages in saline-treated animals.


CONCLUSIONS
To the best of our knowledge, this is the first report of stimulation of arteriogenesis in the brain. The subcutaneous application of GM-CSF led to functional improvement of brain hemodynamic parameters.
Buschmann
Ivo R
IR
Albert Ludwigs University, Research Group for Experimental and Clinical Arteriogenesis, Department for Cardiology and Angiology, Breisacher Strasse 66, Freiburg im Breisgau, Germany. buschmann@med1.ukl.uni-freiburg.de
Busch
Hans-Jörg
HJ
Mies
Günter
G
Hossmann
Konstantin-Alexander
KA
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002455:Cell Division; D002536:Cerebral Arteries / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003097:Collateral Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D008264:Macrophages / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014654:Vascular Patency / Q000187:drug effects
D016178:Granulocyte-Macrophage Colony-Stimulating Factor