Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1567-1572
Published online before print September 5, 2002, doi: 10.1161/01.ATV.0000036417.43987.D8
Published online before print September 5, 2002, doi: 10.1161/01.ATV.0000036417.43987.D8
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© 2002 American Heart Association, Inc.
Vascular Biology |
Bone Marrow–Derived Progenitor Cells Modulate Vascular Reendothelialization and Neointimal Formation
Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition
From the Medizinische Klinik und Poliklinik, Innere Medizin III (N.W., U.L., M.B., G.N.), Universität des Saarlandes, Homburg/Saar, Germany, and Experimentelle Neurologie (J.P., M.E., U.D.), Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Berlin, Germany.
Correspondence to Dr Georg Nickenig, Medizinische Klinik und Poliklinik, Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany. E-mail nickenig{at}med-in.uni-sb.de
Objective— Atherosclerosis and restenosis after vascular injury are both characterized by endothelial dysfunction, apoptosis, inappropriate endothelialization, and neointimal formation. Bone marrow–derived endothelial progenitor cells have been implicated in neovascularization, resulting in adult blood vessel formation. Despite the anticipated stem cell plasticity, the role of bone marrow–derived endothelial progenitor cells has not been clarified in vascular lesion development.
Methods and Results— We investigated vascular lesion formation in mice after transplantation of bone marrow transfected by means of retrovirus with enhanced green fluorescent protein. Carotid artery injury was induced, resulting in neointimal formation. Fluorescence microscopy and immunohistological analysis revealed that bone marrow–derived progenitor cells are involved in reendothelialization of the vascular lesions. Treatment with rosuvastatin (20 mg/kg body wt per day), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, enhanced the circulating pool of endothelial progenitor cells, propagated the advent of bone marrow–derived endothelial cells in the injured vessel wall, and, thereby, accelerated reendothelialization and significantly decreased neointimal formation.
Conclusions— Vascular lesion development initiated by endothelial cell damage is moderated by bone marrow–derived progenitor cells. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibition promotes bone marrow–dependent reendothelialization and diminishes vascular lesion development. These findings may help to establish novel pathophysiological concepts and therapeutic strategies in the treatment of various cardiovascular diseases.
Key Words: endothelium • endothelial progenitor cells • vascular injury • neointima • 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition
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|
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|
|
|
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|
|
|
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|
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|
|
|
|
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|
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|
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|
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|
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|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 L.G Melo, M Gnecchi, A.S Pachori, K Wang, and V.J Dzau Gene- and cell-based therapies for cardiovascular diseases: current status and future directions Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E24 - E35. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Gulati, D. Jevremovic, T. A. Witt, L. S. Kleppe, R. G. Vile, A. Lerman, and R. D. Simari Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H512 - H517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
F.M Sacks Do statins play a role in the early management of the acute coronary syndrome? Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A32 - A36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
S. Fujiyama, K. Amano, K. Uehira, M. Yoshida, Y. Nishiwaki, Y. Nozawa, D. Jin, S. Takai, M. Miyazaki, K. Egashira, et al. Bone Marrow Monocyte Lineage Cells Adhere on Injured Endothelium in a Monocyte Chemoattractant Protein-1-Dependent Manner and Accelerate Reendothelialization as Endothelial Progenitor Cells Circ. Res., November 14, 2003; 93(10): 980 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, Z. Zhang, F. Davison, and Y. Hu Circulating Progenitor Cells Regenerate Endothelium of Vein Graft Atherosclerosis, Which Is Diminished in ApoE-Deficient Mice Circ. Res., October 17, 2003; 93 (8): e76 - e86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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