Crucial role of stromal cell-derived factor-1alpha 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.


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-1alpha 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-1alpha. Systemic injection of isolated PBPCs after vascular injury demonstrated their recruitment to neointimal lesions, where they can adopt an SMC-like phenotype.


CONCLUSIONS
SDF-1alpha 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-1alpha-dependent recruitment of circulating SMC progenitor cells.
Department of Molecular Cardiovascular Research, University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany.
Andreas
A
Schober
Sandra
S
Knarren
Michael
M
Lietz
Elisa A
EA
Lin
Christian
C
Weber
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000950:Antigens, Ly / Q000096:biosynthesis; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019070:Cell Lineage; D002469:Cell Separation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D001057:Apolipoproteins E; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins