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

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.