on January 26, 2006
Published online before print January 26, 2006, doi: 10.1161/01.ATV.0000205607.98538.9a
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on June 6, 2005
Accepted on December 15, 2005
Granulocyte Colony-Stimulating Factor-Mobilized Circulating c-Kit+/Flk-1+ Progenitor Cells Regenerate Endothelium and Inhibit Neointimal Hyperplasia After Vascular Injury
Michitaka Takamiya ;
From the Department of Cardiovascular Medicine (M.T., M.O., N.U., K.T., T.N., K.Z., E.A., T. Tatsumi, T. Takahashi, H.M.), Kyoto Prefectural University School of Medicine, Japan; Department of Pharmacology (D.J., S.T., M.M.), Osaka Medical College, Takatsuki, Japan; Pharmacobioregulation Research Laboratory (Y.N.), Taiho Pharmaceutical Co. Ltd, Saitama, Japan; and Department of Pathology II (Y.A.), Kansai Medical University, Moriguchi, Japan.
* To whom correspondence should be addressed. E-mail: okigakim{at}koto.kpu-m.ac.jp.
Background--Granulocyte colony-stimulating factor (G-CSF) treatment was shown to inhibit neointimal formation of balloon-injured vessels, whereas neither the identification of progenitor cells involved in G-CSF-mediated endothelial regeneration with a bone marrow (BM) transplant experiment nor the functional properties of regenerated endothelium have been studied.
Methods and Results--Recombinant human G-CSF (100 µg/kg per day) was injected daily for 14 days starting 3 days before balloon injury in the rat carotid artery. Neointimal formation of denuded vessels on day 14 was markedly attenuated by G-CSF (39% versus the control; P<0.05). Endothelial cell-specific immunostaining revealed an enhancement of re-endothelialization (1.8-fold increase versus the control; P<0.05) and inhibition of extravasation of Evans Blue dye (47%; P=0.02). The regenerated endothelium exhibited acetylcholine-mediated vasodilatation in NO-dependent manner. G-CSF increased the circulating c-Kit+/Flk-1+ cells (9.1-fold; P<0.02), which showed endothelial properties in vitro (AcLDL uptake and lectin binding) and incorporated into the regenerated endothelium in vivo. A BM replacement experiment with green fluorescence protein (GFP)-overexpressing cells showed that BM-derived GFP+/CD31+ endothelial cells occupied 39% of the total luminal length in the G-CSF-mediated neo-endothelium (2% in the control).
Conclusion--The G-CSF-induced mobilization of BM-derived c-Kit+/Flk-1+ cells contributes to endothelial regeneration, and this cytokine therapy may be a feasible strategy for the promotion of re-endothelialization after angioplasty.
Key words: restenosis • endothelium • carotid artery • cytokines • vascular biology
This article has been cited by other articles:
 |
|
 |
|
  A. Schober Chemokines in Vascular Dysfunction and Remodeling Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1950 - 1959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sugiura, T. Kondo, Y. Kureishi-Bando, Y. Numaguchi, O. Yoshida, Y. Dohi, G. Kimura, R. Ueda, T. J. Rabelink, and T. Murohara Nifedipine Improves Endothelial Function: Role of Endothelial Progenitor Cells Hypertension, September 1, 2008; 52(3): 491 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. E. Toth, R. R. Leker, T. Shahar, S. Pastorino, I. Szalayova, B. Asemenew, S. Key, A. Parmelee, B. Mayer, K. Nemeth, et al. The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia Blood, June 15, 2008; 111(12): 5544 - 5552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Ince, M Valgimigli, M Petzsch, J S. de Lezo, F Kuethe, S Dunkelmann, G Biondi-Zoccai, and C A Nienaber Cardiovascular events and re-stenosis following administration of G-CSF in acute myocardial infarction: systematic review and meta-analysis Heart, May 1, 2008; 94(5): 610 - 616. [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]
|
|
|
|
 |
|
 R. M Cubbon, A. Rajwani, and S. B Wheatcroft The impact of insulin resistance on endothelial function, progenitor cells and repair Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 103 - 111. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Ince, T. C. Rehders, S. Kische, S. Drawert, E. Adolf, T. Kleinfeldt, M. Petzsch, and C. A. Nienaber G-CSF in the setting of acute myocardial infarction Eur. Heart J. Suppl., December 1, 2006; 8(suppl_H): H40 - H45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Fadini, S. Sartore, M. Albiero, I. Baesso, E. Murphy, M. Menegolo, F. Grego, S. Vigili de Kreutzenberg, A. Tiengo, C. Agostini, et al. Number and Function of Endothelial Progenitor Cells as a Marker of Severity for Diabetic Vasculopathy Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 2140 - 2146. [Abstract] [Full Text] [PDF]
|
|