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Granulocyte Colony-Stimulating Factor Improves Cerebrovascular Reserve Capacity by Enhancing Collateral Growth in the Circle of Willis

Duelsner A.a · Gatzke N.a · Glaser J.a · Hillmeister P.a · Li M.a · Lee E.-J.a · Lehmann K.a · Urban D.b · Meyborg H.b · Stawowy P.b · Busjahn A.c · Nagorka S.a · Bondke Persson A.d · Buschmann I.R.a
aDepartment of Internal Medicine, Cardiology and Angiology, Richard Thoma Laboratories for Arteriogenesis, Center for Cardiovascular Research and Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin, bDepartment of Internal Medicine/Cardiology, German Heart Center Berlin, cHealthTwiSt GmbH Berlin, and dInstitute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany Cerebrovasc Dis 2012;33:419–429 (DOI:10.1159/000335869)

Abstract

Background and Purpose: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. Methods: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 µg/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. Results: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 µg/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 µg/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 ± 2 to 12 ± 6%) and rats (3 ± 4 to 19 ± 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 ± 7–271 ± 57 µm; contralateral: 208 ± 11–252 ± 28 µm) and in mice the diameter of anterior cerebral arteries (185 ± 15–222 ± 12 µm) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 ± 2%) was diminished following CCAO (7 ± 4%) and G-CSF treatment (4 ± 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. Conclusion: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication.

 

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