title: Stem cell factor deficiency is vasculoprotective: unraveling a new therapeutic potential of imatinib mesylate.
abstract: Evidence suggests that bone marrow (BM) cells may give rise to a significant proportion of smooth muscle cells (SMCs) that contribute to intimal hyperplasia after vascular injury; however, the molecular pathways involved and the timeline of these events remain poorly characterized. We hypothesized that the stem cell factor (SCF)/c-Kit tyrosine kinase signaling pathway is critical to neointimal formation by BM-derived progenitors. Wire-induced femoral artery injury in mice reconstituted with wild-type BM cells expressing yellow fluorescent protein was performed, which revealed that 66+/-12% of the SMCs (alpha-smooth muscle actin-positive [alphaSMA(+)] cells) in the neointima were from BM. To characterize the role of the SCF/c-Kit pathway, we used c-Kit deficient W/W(v) and SCF-deficient Steel-Dickie mice. Strikingly, vascular injury in these mice resulted in almost a complete inhibition of neointimal formation, whereas wild-type BM reconstitution of c-Kit mutant mice led to neointimal formation in a similar fashion as wild-type animals, as did chronic administration of SCF in matrix metalloproteinase-9-deficient mice, a model of soluble SCF deficiency. Pharmacological antagonism of the SCF/c-Kit pathway with imatinib mesylate (Gleevec) or ACK2 (c-Kit antibody) also resulted in a marked reduction in intimal hyperplasia. Vascular injury resulted in the local upregulation of SCF expression. c-Kit(+) progenitor cells (PCs) homed to the injured vascular wall and differentiated into alphaSMA(+) cells. Vascular injury also caused an increase in circulating SCF levels which promoted CD34(+) PC mobilization, a response that was blunted in mutant and imatinib mesylate-treated mice. In vitro, SCF promoted adhesion of BM PCs to fibronectin. Additionally, anti-SCF antibodies inhibited adhesion of BM PCs to activated SMCs and diminished SMC differentiation. These data indicate that SCF/c-Kit signaling plays a pivotal role in the development of neointima by BM-derived PCs and that the inhibition of this pathway may serve as a novel therapeutic target to limit aberrant vascular remodeling.
authors.affiliation: Cardiology and Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Nicole
authors.initials: N
authors.lastname: Anderson
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Paul E
authors.initials: PE
authors.lastname: Szmitko
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Cherng
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Shafie
authors.initials: S
authors.lastname: Fazel
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D005263:Femoral Artery / Q000293:injuries*; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D000068877:Imatinib Mesylate; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D019089:Stem Cell Factor / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D017539:Tunica Intima / Q000254:growth & development*
chemical_list: D001549:Benzamides; D005353:Fibronectins; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D020780:Matrix Metalloproteinase 9