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(Circulation Research. 2006;99:617.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Stem Cell Factor Deficiency Is Vasculoprotective

Unraveling a New Therapeutic Potential of Imatinib Mesylate

Chao-Hung Wang, Nicole Anderson, Shu-Hong Li, Paul E. Szmitko, Wen-Jing Cherng, Paul W.M. Fedak, Shafie Fazel, Ren-Ke Li, Terrence M. Yau, Richard D. Weisel, William L. Stanford, Subodh Verma

From Cardiology and Internal Medicine (C.-H.W., W.-J.C.), Chang Gung Memorial Hospital, Keelung, Chang Gung University College of Medicine, Taiwan; the Institute of Medical Science (N.A., W.L.S.), Department of Internal Medicine (P.E.S.), Institute of Biomaterials and Biomedical Engineering (W.L.S.), and Department of Chemical Engineering and Applied Chemistry (W.L.S.), University of Toronto, Canada; Cardiac Surgery (C.-H.W., S.-H.L., P.W.M.F., S.F., R.-K.L., T.M.Y., R.D.W.), Toronto General Hospital, Canada; and Division of Cardiac Surgery (S.V.), St. Michael’s Hospital, Toronto, Canada.

Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, St. Michael’s Hospital, 8 Fl, Bond Wing, 30 Bond St, Toronto, ON M5B 1W8, Canada. E-mail Subodh.Verma{at}Sympatico.ca, or to William L. Stanford, University of Toronto, Toronto, Canada. E-mail william.stanford@utoronto.ca

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 (-smooth muscle actin-positive [SMA⁺] 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 SMA⁺ 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.

Key Words: vascular remodeling • genetic mice models • vascular biology • vascular smooth muscle

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