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. 2004 Aug 24;101(34):12730-5.
doi: 10.1073/pnas.0404880101. Epub 2004 Aug 11.

Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke

Edda Schneeloch  1 , Günter Mies, Hans-Jörg Busch, Ivo R Buschmann, Konstantin-Alexander Hossmann
Affiliations

Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke

Edda Schneeloch et al. Proc Natl Acad Sci U S A. .

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a powerful arteriogenic factor in the hypoperfused rat brain. To test the pathophysiological relevance of this response, the influence of GM-CSF on brain energy state was investigated in a model of hemodynamic stroke. Sprague-Dawley rats were submitted to three-vessel (bilateral vertebral and unilateral common carotid artery) occlusion (3-VO) to induce unilaterally accentuated brain hypoperfusion. One week later, hemodynamic stroke was induced by additional lowering of arterial blood pressure. Experiments were terminated by in situ freezing of the brain. ATP was measured in cryostat sections by using a bioluminescence method. The use of 3-VO, in combination with 15 min of hypotension of 50, 40, or 30 mmHg, did not produce disturbances of energy metabolism, however, focal areas of ATP depletion were unilaterally detected after 3-VO, in combination with 15 min of hypotension of 20 mmHg. Treating such animals with GM-CSF (40 microg.kg(-1).d(-1)) during the 1-week interval between 3-VO and induced hypotension significantly reduced the hemispheric volume of energy depletion from 48.8 +/- 44.2% (untreated group, n = 10) to 15.8 +/- 17.4% (treated group, n = 8, P = 0.033). GM-CSF-induced arteriogenesis is another approach to protect the brain against ischemic injury.

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Figures

Fig. 1.
Fig. 1.
Recording of CBF from ipsilateral (Top) and contralateral (Middle) parietal cortex by LDF during 3-VO in combination with hemorrhagic hypotension (Bottom). During hypotension, LDF decline is more pronounced in the ipsilateral hemisphere, i.e., on the side of carotid artery occlusion (20% flow level and 20 mmHg pressure level are indicated by the dotted lines).
Fig. 2.
Fig. 2.
Incidence maps of ATP depletion at the end of hemorrhagic hypotension in combination with 3-VO. Comparison of 15 min of hypotension at 20 mmHg (Left) with 30 min of hypotension at 30 mmHg (Right). Areas of disturbed metabolism are outlined on coronal cryostat sections of three animals per group and superimposed to demonstrate the regional incidence of energy failure. Note the strict lateralization of energy failure in the left hemisphere during hypotension at 20 mmHg.
Fig. 3.
Fig. 3.
Effect of 15 min of hemorrhagic hypotension on CBF at 1 week after 3-VO. Comparison of untreated animals with animals treated with GM-CSF (40 μg·kg-1·d-1). Representative iodo[14C]antipyrine autoradiograms of brain cryostat sections at the level of caudate-putamen obtained either at normotension (above) or at the end of 15 min of hypotension (below). Note the lesser reduction of blood flow in the left hemisphere of treated animals.
Fig. 4.
Fig. 4.
Effect of 15 min of hypotension on ATP content at 1 week after 3-VO. Comparison of untreated animals with animals treated with GM-CSF (40 μg·kg-1·d-1). ATP-dependent bioluminescence was measured during hypotension at three coronal levels, passing through the frontal part of caudateputamen, dorsal hippocampus, and globus pallidus. Note the marked reduction of energy failure in the treated animal.
Fig. 5.
Fig. 5.
Incidence maps of ATP depletion in animals submitted to 3-VO in combination with 15 min of hemorrhagic hypotension at 20 mmHg (for explanation, see Fig. 2). Comparison of untreated (n = 10) with GM-CSF-treated animals (n = 8). Note the marked reduction of areas with ATP depletion, despite similar blood pressure levels during hypotension (Left Lower). Calculation of injury volume by integration of ATP-depleted areas at six coronal levels reveals significant (*, P < 0.05) volume reduction after treatment (means ± SD, Right Lower).
Fig. 6.
Fig. 6.
Measurements of regional ATP content (means ± SD) by quantitative bioluminescence imaging in various cortical and subcortical regions of the hemisphere ipsilateral to the left common carotid artery occlusion. White bars, untreated animals (n = 10); black bars, GM-CSF-treated animals (n = 8). The P values were calculated by Student's t test and were assigned in the following manner: +, P < 0.005; ++, P < 0.001 next to the white bar designates comparison between ipsilateral and contralateral regions of untreated animals; §, P < 0.005 next to the black bars indicates comparison between ipsilateral and contralateral regions of GM-CSF-treated animals; *, P < 0.05 next to the black bars represents difference between ipsilateral GM-CSF-treated and ipsilateral untreated animals.
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