Crucial Role of Stromal Cell–Derived Factor-1α in Neointima Formation After Vascular Injury in Apolipoprotein E–Deficient Mice

Abstract

Background— Recent evidence indicates that stromal cell–derived factor-1α (SDF-1α) 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-1α in neointimal formation after vascular injury. Methods and Results— SDF-1α 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-1α staining was mostly confined to smooth muscle cells (SMCs). Furthermore, SDF-1α plasma levels peaked 1 day after vascular injury. Treatment of apoE −/− mice after carotid injury with a neutralizing SDF-1α 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.