Granulocyte Colony-Stimulating Factor Enhances Arteriogenesis and Ameliorates Cerebral Damage in a Mouse Model of Ischemic Stroke

Abstract

Background and Purpose-Enhancing collateral artery growth is a potent therapeutic approach to treat cardiovascular ischemic disease from occlusive artery. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has gained attention for its ability to promote arteriogenesis, ameliorating brain damage, by the mechanisms involving monocyte upregulation. However, the recent clinical study testing its efficacy in myocardial ischemia has raised the question about its safety. We tested alternative colony-stimulating factors for their effects on collateral artery growth and brain protection. Methods-Brain hypoperfusion was produced by occluding the left common carotid artery in C57/BL6 mice. After the surgery, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, or GM-CSF (100 g/kg/day) was administered daily for 5 days. The angioarchitecture for leptomeningeal anastomoses and the circle of Willis were visualized after the colony-stimulating factor treatment. Circulating blood monocytes and Mac-2-positive cells in the dorsal surface of the brain were determined. A set of animals underwent subsequent ipsilateral middle cerebral artery occlusion and infarct volume was assessed. Results-Granulocyte colony-stimulating factor as well as GM-CSF promoted leptomeningeal collateral growth after common carotid artery occlusion. Both granulocyte colony-stimulating factor and GM-CSF increased circulating blood monocytes and Mac-2-positive cells in the dorsal brain surface, suggesting the mechanisms coupled to monocyte upregulation might be shared. Infarct volume after middle cerebral artery occlusion was reduced by granulocyte colony-stimulating factor, similarly to GM-CSF. Macrophage colony-stimulating factor showed none of theses effects. Conclusions-Granulocyte colony-stimulating factor enhances collateral artery growth and reduces infarct volume in a mouse model of brain ischemia, similarly to GM-CSF. (Stroke. 2011;42:770-775.)

Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection

“…G-CSF is a glycoprotein originally found to be involved in the proliferation, survival, and maturation of granulocytes but later shown to confer neuroprotection against ischemic insult by directly binding its corresponding receptor to neurons (Schabitz et al, 2003). G-CSF and its receptor have been shown to be induced upon brain ischemia in the peri-ischemic area (Schneider et al, 2005), and G-CSF has been suggested to serve as a defense mechanism against ischemic cell death by multiple mechanisms (Sugiyama et al, 2011;Solaroglu et al, 2009). Even though the AXIS-2 clinical trial for G-CSF treatment failed to show efficacy in humans, the mechanisms by which G-CSF could mediate neuroprotection in elderly patients with comorbidities with elevated systemic inflammatory burden have not been modeled in preclinical studies.…”

Intravascular Perfusion of Carbon Black Ink Allows Reliable Visualization of Cerebral Vessels

“…Although perfusion of latex has originally been carried out through the ascending aorta 2,3 , alternative routes of perfusion are also reported including the left ventricle 7,8 or the common carotid artery 9 . We found no significant difference in the outcomes following perfusion through either the ascending aorta or the left ventricle (unpublished observations).…”

Understanding and Augmenting Collateral Blood Flow During Ischemic Stroke

“…Prophylactic injection of GM-CSF in rats for 6 weeks prior to bilateral common carotid artery occlusion has been shown to attenuate functional impairment of cerebrovascular reserve capacity and increase leptomeningeal collateral density (Schneider et al, 2007). A recent study demonstrated that five days of daily GM-CSF or G-CSF administered to C57/BL6 mice after unilateral occlusion of the common carotid artery also promoted leptomeningeal collateral growth and decreased infarct volume (Sugiyama et al, 2011). A subset of these animals received MCAo seven days after common carotid occlusion.…”

“…While mild induced hypertension may be neuroprotective, it is important to note that chronic hypertension worsens stroke outcome (Aslanyan et al, 2003;Geeganage et al, 2011;Toyoda et al, 2009), possibly due to inhibition of collateral blood flow. In spontaneously hypertensive rats, compensatory growth of leptomeningeal collaterals in response to chronic cerebral hypoperfusion is impaired relative to normotensive rats, though this compensatory growth is restored by anti-hypertensive therapies (Omura-Matsuoka et al, 2011). Clinically, blood pressure is often elevated during MCAo and clinical trials have not demonstrated unequivocal beneficial results in neurological outcome after stroke (Liebeskind, 2003).…”