Granulocyte-Macrophage Colony-Stimulating Factor–Induced Vessel Growth Restores Cerebral Blood Supply After Bilateral Carotid Artery Occlusion

Abstract

Background and Purpose— Hemodynamic compromise due to occlusive cerebrovascular disease is associated with an increased stroke risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been suggested to stimulate collateral blood vessel growth in various models of hemodynamic compromise. The purpose of this study was to investigate the effects of GM-CSF on cerebral hemodynamics and vessel growth in a rat model of chronically impaired cerebral blood flow (CBF). Methods— Male Sprague-Dawley rats underwent sequential bilateral carotid artery occlusion (BCO) and were treated with GM-CSF or saline for 6 weeks. Sham-occluded animals served as a control group. Baseline CBF was measured by iodo[ 14 C]antipyrine autoradiography, and cerebrovascular reserve capacity was assessed by laser-Doppler flowmetry after application of 20 mg/kg body weight acetazolamide. The capillary density and arterioles immunopositive for α-smooth muscle actin were counted on brain sections. The cerebral angioarchitecture was visualized with a latex perfusion technique. Results— Baseline CBF as measured by iodo[ 14 C]antipyrine autoradiography was not affected by BCO. The cerebrovascular reserve capacity, however, was significantly impaired 1 week after BCO. CBF and cerebrovascular reserve capacity recovered completely in GM-CSF–treated animals but not in solvent-treated animals. Histologic analysis of the hippocampus revealed integrity of the hypoxia-vulnerable neurons in all animals. The capillary density showed a very mild increase in GM-CSF–treated animals. However, the number of intraparenchymal and leptomeningeal arterioles was significantly higher in GM-CSF–treated animals than in both other groups. Conclusions— Long-term GM-CSF treatment in a BCO model in rats leads to restoration of impaired cerebral hemodynamics and accompanies structural changes in the resistance-vessel network.

Endothelial Progenitor Cells Augment Collateralization and Hemodynamic Rescue in a Model of Chronic Cerebral Ischemia

“…This increase of the number of anastomoses leads to an increase of the total cross-sectional vessel area and thus, may improve the total conductance of the brain vasculature. Although this finding is in line with our previous report, 5 it differs from published mouse model studies, 34,35 where a primary increase in the diameter but not the number of anastomoses was detected. Possibly, this difference in leptomeningeal outgrowth may be due to differences in the animal strain but more importantly, different vessel occlusion techniques in these studies may influence collateral outgrowth due to different perfusion pressure gradients across the leptomeningeal vasculature.…”

“…31 Compared with previous studies where a single hematopoietic stem cell factor (granulocyte macrophage colony-stimulating factor) was administered, 4,5 the augmented collateralization after treatment with e-EPC could be due to the different treatment modalities, since e-EPC harbor the potential for expression of multiple protein growth factors. 20 Nevertheless, the application of a different vessel occlusion model (2-VO) in our previous study 5 as well as differences in the observation time points somewhat limit comparability. Leptomeningeal anastomoses are the main collaterals to compensate for restricted blood flow distal to the Circle of Willis.…”

“…Arteriogenesis, however, is characterized as the positive outgrowth of preexisting collaterals at the level of the conductance or resistance vasculature, which coincides with an augmentation of collateral flow. 4,5,19 Against this background, we investigated EPC e-EPC treatment of cerebral hemodynamic compromise N Hecht et al as a novel treatment modality for chronic cerebral hypoperfusion because EPC secrete various proangiogenic growth factors, [20][21][22] which may be beneficial in chronic steno-occlusive cerebrovascular disease where neovascularization in terms of collateral vessel growth is required in regions apart from the ischemic tissue. Moreover, EPC are characterized by high plasticity and promigratory activity with the potential for active incorporation into a developing vasculature.…”

“…3 This concept of therapeutic stimulation of collateral vessel growth has recently been adapted to the cerebrovascular system. 4,5 In contrast, postnatal vasculogenesis describes the de novo formation of blood vessels through migration and differentiation of circulating endothelial progenitor cells (EPC).…”

Understanding and Augmenting Collateral Blood Flow During Ischemic Stroke

“…In fact, a number of groups have identified a neuroprotective role for G-CSF and GM-CSF administered before or after ischemia in rodent models (Todo et al, 2008;Nakagawa et al, 2006;Schäbitz et al, 2008), likely in part due to its upregulation of the formation of collateral vascular channels. 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).…”