Artikel
Stimulation of angio- and arteriogenesis and cerebral blood flow in a rat model of chronic mild impairment of the cerebral perfusion
Stimulation von Angio- ung Arteriogenese und des zerebralen Blutflusses in einem Rattenmodell chronisch leicht verminderter zerebraler Perfusion
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Autoren
Veröffentlicht: | 23. April 2004 |
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Gliederung
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Objective
To study the influence of long-term therapy with a recombinant granulocyte-macrophage colony stimulating factor (GM-CSF, Leukomax®) on regional cerebral blood flow (rCBF) and the morphology of the cerebral microvascular network in an animal model of chronic mild cerebral hypoperfusion.
Methods
Experiments were performed in male Sprague-Dawley rats with surgery and measurements performed under isoflurane anaesthesia. On day one, sagittal grooves were drilled over both temporal hemispheres outreaching the coronal and lambda suture. In these grooves rCBF was repeatedly measured using scanning Laser-Doppler flowmetry (LDF) in at least 80 different points. Animals underwent right-sided intraluminal occlusion of the internal carotid artery (ICA) on day one, followed by left-sided occlusion on day seven. The animals received a subcutaneous injection of 10 μg/kg Leukomax (R) (treatment group) or 0.2 ml/kg saline (control group) once a day for seven weeks starting on day one. LDF measurements were performed weekly. After seven weeks the rats were perfused with Evan's Blue (EB). Serially cut coronal brain sections were prepared and scanned for capillary density using EB-fluorescence. Adjacent brain sections were with Alpha-smooth muscle actin (alpha-SMA) antibody to evaluate the number of arterioles and small arteries.
Results
The acute drop of CBF induced by ICA occlusion on days one and seven did not differ between treated and control animals. The CBF recovered within a week after ICA occlusion in control animals, but rose steadily above basal levels in GM-CSF treated animals. At the end of the experiments, values were 35% higher than baseline (p<0.05). There were no signs of apoptosis, or decrease in cell density in the hippocampus at the end of the experiments, indicating that no ischemic brain damage had occurred. Capillary density was slightly yet significantly higher in motorcortex areas of treated animals (p<o.o5 vs. control group). The number of alpha-SMA positive vessels increased throughout all brain sections (+35% compared to control animals) after seven-week treatment and was up to 60% higher in individual brain regions.
Conclusions
These results suggest that systemic application of GM-CSF results in enhanced arteriogenesis and stimulation of angiogenesis in a state of chronic mild cerebral hypoperfusion. The underlying mechanisms and the role of macrophages are currently under investigation. The present results may also be clinically relevant and promise a new therapeutic approach, in states of, yet compensated compromised cerebral hypoperfusion, such as, ICA stenosis.