Crucial role of stromal cell-derived factor-1α in neointima formation after vascular injury in apolipoprotein E-deficient mice

Background-Recent evidence indicates that stromal cell-derived factor-1alpha (SDF-1alpha) is expressed in human atherosclerotic plaques, whereas high plasma levels are clinically associated with stable coronary artery disease. Herein, we investigate the involvement of SDF-1alpha in neointimal formation after vascular injury. Methods and Results-SDF-1alpha was detected by immunohistochemistry in carotid arteries of apolipoprotein E-deficient (apoE(-/-)) mice at various stages of neointima formation after wire-induced injury. Double immunofluorescence revealed that SDF-1alpha staining was mostly confined to smooth muscle cells (SMCs). Furthermore, SDF-1alpha plasma levels peaked 1 day after vascular injury. Treatment of apoE(-/-) mice after carotid injury with a neutralizing SDF-1alpha monoclonal antibody for 3 weeks reduced neointimal lesion area by 44% (n=5, P<0.05) compared with isotype control. In SDF-1α antibody-treated apoE(-/-) mice, neointimal SMC content was decreased (21.7±2% versus 39.4±4%, n=5, P=0.005), whereas the relative content of neointimal macrophages remained unchanged. As shown by flow cytometry, carotid injury resulted in a marked expansion of circulating Sca-1(+) lineage(-) progenitor cells (PBPCs) in the peripheral blood of apoE(-/-) mice after 1 day, which was mediated by SDF-1α. Systemic injection of isolated PBPCs after vascular injury demonstrated their recruitment to neointimal lesions, where they can adopt an SMC-like phenotype. Conclusions-SDF-1α plays an instrumental role in neointimal formation after vascular injury in apoE(-/-) mice by regulating neointimal SMC content. This contribution appears to be attributable to SDF-1α-dependent recruitment of circulating SMC progenitor cells.