Granulocyte Colony-Stimulating Factor Mobilizes Functional Endothelial Progenitor Cells in Patients With Coronary Artery Disease

Abstract

Objective— Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Methods and Results— Sixteen CAD patients had reduced CD34 + /CD133 + (0.0224±0.0063% versus 0.121±0.038% mononuclear cells [MNCs], P <0.01) and CD133 + /VEGFR-2 + cells, consistent with EPC phenotype (0.00033±0.00015% versus 0.0017±0.0006% MNCs, P <0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2±1/well) compared with 16 healthy subjects at high risk (13±4/well, P <0.05) or 14 at low risk (22±3/well, P <0.001) for CAD. G-CSF 10 μg/kg per day for 5 days increased CD34 + /CD133 + cells from 0.5±0.2/μL to 59.5±10.6/μL and CD133 + / VEGFR-2 + cells from 0.007±0.004/μL to 1.9±0.6/μL (both P <0.001). Also increased were CD133 + cells that coexpressed the homing receptor CXCR4 (30.4±8.3/μL, P <0.05). Endothelial cell-forming clusters in 10 patients increased to 27±9/well after treatment ( P <0.05), with a decline to 9±4/well at 2 weeks ( P =0.06). Conclusions— Despite reduced EPCs compared with healthy controls, patients with CAD respond to G-CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out-growth in culture.

Flow cytometric measurement of circulating endothelial cells: The effect of age and peripheral arterial disease on baseline levels of mature and progenitor populations

“…Also, the number of risk factors in their study was significantly correlated with a reduction of EPC levels (R ¼ À0.394, P ¼ 0.002) and CD34-/KDR-positive cells (R ¼ À0.537, P < 0.001) thus indicating individual confounding variables exist among patients. Pharmaceutical compounds also appear to stimulate (21) and perhaps inhibit EPC mobilization from the bone marrow (22,23). The purpose of our study was to design and test a strategy of measuring multiple populations of cells using multiparameter flow cytometry and not to clinically evaluate the effects of risk factors or medications on EPC number.…”

Appropriate doses of Granulocyte-Colony Stimulating Factor Reduced Atherosclerotic Plaque Formation and Increased Plaque Stability in Cholesterol-Fed Rabbits

“…On the other hand, administration of G-CSF may worsen plaque formation and restenosis in coronary arteries. Enhancement of increased circulating granulocytes with G-CSF has been shown to induce adverse cardiovascular events, including acute coronary syndrome [18][19][20] . Kang et al 18) reported that G-CSF treatment might increase the progression of atherosclerotic plaque and in-stent restenosis in patients treated with primary percutaneous coronary intervention.…”

Therapeutic Angiogenesis With Intramuscular Injection of Low-Dose Recombinant Granulocyte-Colony Stimulating Factor

“…6 -9 However, it is known that G-CSF enhances the number of circulating granulocytes that potentially induces adverse cardiovascular events including acute coronary syndrome. 10,11 In earlier studies, Bussolino et al demonstrated that G-CSF stimulated angiogenic functions of mature endothelial cells (ECs), resulting in enhanced migration, proliferation and tube formation in vitro. 12,13 From the latter findings, we reasoned that low dose of G-CSF injected into local ischemic tissues would enhance neovascularization via direct stimulatory actions on endothelial cells.…”