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  • Title: Stem cell factor deficiency is vasculoprotective: unraveling a new therapeutic potential of imatinib mesylate.
    Author: Wang CH, Anderson N, Li SH, Szmitko PE, Cherng WJ, Fedak PW, Fazel S, Li RK, Yau TM, Weisel RD, Stanford WL, Verma S.
    Journal: Circ Res; 2006 Sep 15; 99(6):617-25. PubMed ID: 16931795.
    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.
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