Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells.
BACKGROUND
Primary and secondary prevention trials suggest that statins possess favorable effects independent of cholesterol reduction. We investigated whether statin therapy may also accelerate reendothelialization after carotid balloon injury.


RESULTS
Simvastatin treatment in 34 male Sprague-Dawley rats accelerated reendothelialization of the balloon-injured arterial segments (reendothelialized area at 2 weeks, 12.3+/-1.8 versus 5.4+/-1.1 mm2, P< 0.01) and resulted in a dose-dependent (0.2 or 1 mg/kg IP) significant reduction in neointimal thickening at 2, 3, and 4 weeks compared with saline-injected controls (n=18). To elucidate the mechanism, we investigated the contribution of bone marrow-derived endothelial progenitor cells (EPCs) by bone marrow transplantation from Tie2/lacZ mice to background mice or nude rats. X-gal staining of mouse carotid artery specimens revealed a 2.9-fold increase in the number of beta-gal-positive cells per square millimeter appearing on the carotid artery luminal surface at 2 weeks, and double-fluorescence immunohistochemistry disclosed a significant 5-fold increase in the number of double-positive cells (beta-gal, isolectin B4) on the luminal surface in carotid arteries of statin-treated nude rats (20+/-3 versus 4+/-1 cells/mm surface length, P<0.005). Statins increased circulating rat EPCs (2.4-fold at 2 weeks and 2.5-fold at 4 weeks, P<0.001) and induced adhesiveness of cultured human EPCs by upregulation of the integrin subunits alpha5, beta1, alpha(v), and beta5 of human EPCs as shown by reverse transcription-polymerase chain reaction and fluorescence-activated cell sorting.


CONCLUSIONS
These findings establish additional mechanisms by which statins may specifically preempt disordered vascular wall pathology and constitute physiological evidence that EPC mobilization represents a functionally relevant consequence of statin therapy.
Walter
Dirk H
DH
Department of Medicine (Cardiovascular Research), St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Rittig
Kilian
K
Bahlmann
Ferdinand H
FH
Kirchmair
Rudolf
R
Silver
Marcy
M
Murayama
Toshinori
T
Nishimura
Hiromi
H
Losordo
Douglas W
DW
Asahara
Takayuki
T
Isner
Jeffrey M
JM
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D016026:Bone Marrow Transplantation; D016893:Carotid Stenosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000254:growth & development*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016023:Integrins / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016023:Integrins; D019821:Simvastatin