on January 4, 2007
Published online before print January 4, 2007, doi: 10.1161/01.ATV.0000257148.01384.7d
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 15, 2006
Accepted on November 27, 2006
Stem Cell Factor Attenuates Vascular Smooth Muscle Apoptosis and Increases Intimal Hyperplasia After Vascular Injury
Chao-Hung Wang *;
From the Division of Cardiology, Department of Internal Medicine (C.-H.W., I.-C.H., A.H., T.-T.C., S.-Y.W., Y.-C.L., W.-J.C.), Chang Gung Memorial Hospital, Keelung; Chang Gung University College of Medicine, Taiwan; the Division of Cardiac Surgery (S.V.), St. Michael’s Hospital, Toronto, Canada; the Division of Cardiac Surgery (C.-H.W., S.V., R.D.W., R.-K.L.), Toronto General Hospital, Toronto, Canada; the Institute of Bioscience and Biotechnology (T.-T.C.), National Taiwan Ocean University; and the Institute of Biomaterials and Biomedical Engineering (W.L.S.), University of Toronto; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada.
* To whom correspondence should be addressed. E-mail: bearty{at}adm.cgmh.org.tw.
Objective--Stem cell factor (SCF) through its cognate receptor, the tyrosine kinase c-kit, promotes survival and biological functions of hematopoietic stem cells and progenitors. However, whether SCF/c-kit interactions exacerbate intimal hyperplasia through attenuating VSMC apoptosis induced by vascular injury has not been thoroughly investigated.
Methods and Results--VSMCs were stimulated with serum deprivation and H2O2 to induce apoptosis. The transcription of c-kit mRNA and the expression of the c-kit protein by VSMCs were estimated by Q-polymerase chain reaction and Western blotting, respectively. The interactions of SCF and c-kit were investigated by in vitro and in vivo experiments. In vitro, H2O2 stimulation significantly induced apoptosis of VSMCs as evidenced by the 3- and 3.2-fold increases of cleaved caspase-3 compared with those in the control group by Western blot and flow cytometric analyses, respectively (P<0.01). Stimulation of apoptosis also caused 3.5- and 9-fold increases in c-kit mRNA transcription and protein expression, respectively, by VSMCs compared with those in the control group. Administration of SCF (10 to 1000 ng/mL) significantly lowered the amount of cleaved caspase-3 in H2O2-treated VSMCs (P<0.01). Specifically, SCF exerted this effect through activating Akt, followed by increasing Bcl-2 and then inhibiting the release of cytochrome-c from the mitochondria to the cytosol. In vivo, the mouse femoral artery was injured with a wire in SCF mutant (Sl/Sld), c-kit mutant (W/Wv), and colony control mice. In colony control mice, confocal microscopy demonstrated that the wire-injury generated a remarkable activation of caspase-3 on medial VSMCs, coinciding with upregulation of c-kit expression. The wire-injury also caused an increase in the expression of SCF on surviving medial VSMCs and cells in the adventitia. The upregulated c-kit expression in the vessel wall also facilitated homing by circulating SCF+ cells. Compared with colony control mice, vascular injury in SCF mutant and c-kit mutant mice caused a higher number of apoptotic VSMCs on day 14 and a lower number of proliferating cells, and resulted in significantly less neointimal formation (P<0.01) on day 28.
Conclusions--The interactions between SCF and the c-kit receptor play an important role in protecting VSMCs against apoptosis and in maintaining intimal hyperplasia after vascular injury.
Key words: apoptosis • c-kit tyrosine kinase • intimal hyperplasia • restenosis • stem cell factor
This article has been cited by other articles:
 |
|
 |
|
  P.-H. Huang, Y.-H. Chen, C.-H. Wang, J.-S. Chen, H.-Y. Tsai, F.-Y. Lin, W.-Y. Lo, T.-C. Wu, M. Sata, J.-W. Chen, et al. Matrix Metalloproteinase-9 Is Essential for Ischemia-Induced Neovascularization by Modulating Bone Marrow-Derived Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1179 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hu and L. M. Colletti Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G45 - G53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-H. Wang, W.-J. Cherng, N.-I Yang, C.-M. Hsu, C.-H. Yeh, Y.-J. Lan, J.-S. Wang, and S. Verma Cyclosporine increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R811 - R818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Diao, S. Guthrie, S.-L. Xia, X. Ouyang, L. Zhang, J. Xue, P. Lee, M. Grant, E. Scott, and M. S. Segal Long-Term Engraftment of Bone Marrow-Derived Cells in the Intimal Hyperplasia Lesion of Autologous Vein Grafts Am. J. Pathol., March 1, 2008; 172(3): 839 - 848. [Abstract] [Full Text] [PDF]
|
|