Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1567-1572
Published online before print September 5, 2002, doi: 10.1161/01.ATV.0000036417.43987.D8
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
22/10/1567    most recent
01.ATV.0000036417.43987.D8v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Werner, N.
Right arrow Articles by Nickenig, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Werner, N.
Right arrow Articles by Nickenig, G.
Related Collections
Right arrow Health policy and outcome research
Right arrow Other Ethics and Policy
Right arrow Cardiovascular imaging agents/Techniques
Right arrow Coagulation and fibronolysis
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1567.)
© 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

Nikos Werner*; Josef Priller*; Ulrich Laufs; Matthias Endres; Michael Böhm; Ulrich Dirnagl; Georg Nickenig

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


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Atherosclerosis leads to serious medical conditions, including coronary heart disease, the main cause of death in the Western world.1 Atherosclerotic lesions are initiated by endothelial cell damage, followed by macrophage adhesion and invasion as well as smooth muscle cell migration and growth.2 If stenosis due to atherosclerosis is treated by balloon angioplasty and/or stent implantation, restenosis of the target vessel is frequently observed.3 This is caused by

See cover and page 1509

endothelial cell damage and rapid neointimal formation, which is mainly composed of proliferating smooth muscle cells.4,5 Thus, despite numerous epidemiological, cellular, and molecular differences, atherosclerosis and restenosis after vascular injury share at least 1 important pathophysiological step: endothelial cell damage followed by an impaired reendothelialization.5,6 It is currently believed that this reendothelialization is controlled by the adjacent endothelial cells within the vessel wall.7

Accumulating evidence indicates that bone marrow–derived cells are involved in repair processes throughout the cardiovascular system.811 Accordingly, endothelial progenitor cells (EPCs) have been implicated in neovascularization in the context of peripheral arterial disease as well as coronary heart disease.8,1216 In addition, bone marrow–derived cells may help to reestablish myocardial tissue after myocardial infarction.10,15,1721

Little is known about the relevance of EPCs in the development and cure of atherosclerotic lesions. It is unclear whether bone marrow–derived cells are involved in the reendothelialization and neointimal formation causing restenosis after vascular injury and whether these events can be modulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, which are thought to influence the release of progenitor cells from the bone marrow.22,23

In the present study, mice with green fluorescent protein (GFP)-marked bone marrow were subjected to carotid artery injury to elucidate the role of the bone marrow in reendothelialization and neointimal formation. Furthermore, the effect of rosuvastatin versus placebo on circulating EPCs and reendothelialization was evaluated.


*    Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Retroviral Gene Transfer and Bone Marrow Transplantation
Reconstitution of hematopoiesis with GFP-marked bone marrow cells was performed as described previously.24,25 Briefly, bone marrow was harvested from 8- to 10-week-old male C57/BL6 mice 2 days after treatment with 5-fluorouracil (Sigma Chemical Co). Bone marrow cells were stimulated in DMEM/15% FCS supplemented with 20 ng/mL recombinant murine interleukin-3, 50 ng/mL human interleukin-6 (PromoCell), and 50 ng/mL rat stem cell factor (generously provided by Amgen, Munich, Germany) for 48 hours. Subsequently, bone marrow cells were cocultured with irradiated (13-Gy) viral producer cells. The ecotropic packaging cell line GP+E86 was used for the generation of MGirL22Y retroviral vector particles. The MGirL22Y vector was generated by cloning the enhanced GFP (Clontech) gene upstream from the internal ribosomal entry site from the encephalomyocarditis virus linked to a mutant dihydrofolate reductase gene (L22Y) in a murine stem cell virus vector. The presence of recombinant retrovirus was excluded in assays that used a mus dunni test cell line. After 48 hours of coculture, nonadherent bone marrow cells were rinsed off the producer cell monolayer. Transduced bone marrow cells (5x106) were transplanted by tail vein injection into lethally irradiated 8- to 10-week-old male C57/BL6 mice (11-Gy cumulative dose). Flow cytometric analysis of GFP expression was performed in peripheral blood leukocytes of mice 8 months after transplantation of GFP-expressing bone marrow cells and in leukocytes of control mice that did not receive GFP-labeled bone marrow. Approximately 70% of white blood cells were stably expressing the fluorophore in GFP–bone marrow chimeras. All myeloid and lymphocytic populations were labeled, but the levels of GFP expression varied within lineages. The highest expression was observed in monocytes/macrophages and granulocytes.

Carotid Injury and Treatment
Six months after bone marrow reconstitution, the mice received daily doses of rosuvastatin (Crestor, generously provided by AstraZeneca, Cheshire, UK) at 20 mg/kg body wt subcutaneously. Control animals received a corresponding amount of normal saline. Treatment was started 10 days before carotid injury and was continued until tissue harvesting.

Carotid artery injury was induced as described previously.26 Briefly, the mice were anesthetized with halothane/N2O. By use of a dissecting microscope (MZ6, Leica), the bifurcation of the left carotid artery was exposed via a midline incision of the ventral side of the neck. Two ligatures were placed proximally and distally around the external carotid artery. The distal ligature was then tied off. After temporary occlusion of the internal and common carotid artery with ligatures, a transverse arteriotomy was performed between the ligatures of the external carotid artery to introduce a 0.13-mm-diameter curved flexible wire. The wire was passed 3 times along the common carotid artery in a rotating manner. After removal of the wire, the proximal ligature of the external carotid artery was tied off. Restoration of normal blood flow was confirmed, and the skin was closed with single sutures with the use of 6/0 silk. Animals were allowed to recover, and carotid arteries were harvested after 14 days. All animal procedures were approved and were in accordance with the institutional guidelines.

Vessel Harvesting
After perfusion-fixation with 4% paraformaldehyde, carotid arteries were embedded in Tissue Tek OCT embedding medium (Miles Laboratories), snap-frozen, and stored at -80°C. Samples were sectioned on a Leica cryostat (7 µm) and placed on poly-L-lysine (Sigma)–coated slides for immunohistochemical analysis.

Histochemistry
Cryosections were assessed for endothelial cell markers (von Willebrand factor [vWF], polyclonal antibody, clone A 0082, Dako; vascular endothelial growth factor receptor 2, monoclonal antibody [mAb] A-3, Santa Cruz; and vascular endothelial cadherin, F-8, Santa Cruz), smooth muscle cells (mAb smooth muscle {alpha}-actin, clone 1A4, Sigma), and inflammatory cell markers (mAb Mac-3, clone M3/84; mAb CD45.1, clone A20; Pharmingen) with a direct immunofluorescence method. For light microscopy, a peroxidase-conjugated anti-GFP antibody (mAb GFP, B-2, Santa Cruz) with DAB staining (Dako) or APAAP Mouse Monoclonal IgG (F-8, Santa Cruz) with BCIP/NBT (Dako) was used. Nuclear staining was performed with the use of 4',6-diamidino-2-phenylindole (Dapi, Linaris). Isotype-specific secondary antibodies (Santa Cruz) were used for negative controls. For immunohistochemistry, tissue cryosections were postfixed in 4% formaldehyde for 2 minutes. Slides were preincubated with 0.5% Igepal (Sigma) and 5% normal goat serum (Sigma) for 30 minutes each. The primary antibody was applied for 2 to 3 hours at room temperature or at 4°C overnight, followed by application of the appropriate TRITC-conjugated secondary antibody (Sigma) for 30 minutes. Sections were washed and mounted with fluorescent mounting medium (Dako) for fluorescence microscopic analysis. For morphometric analyses, hematoxylin and eosin staining was performed according to standard protocols. All sections were examined under a Nikon E600 microscope. For morphometric analyses, Lucia Measurement Version 4.6 software (Nikon, Germany) was used to measure external elastic lamina, internal elastic lamina, and lumen circumference, as well as medial and neointimal area of 25 sections per animal. To determine reendothelialization, mice received 50 µL of 5% Evans blue diluted in normal saline by tail vein injection 10 minutes before euthanization, followed by perfusion-fixation. Arteries were opened longitudinally and placed between slides with mounting medium (Dako). After transparency scanning (Nikon SMZ800), stained carotid arteries were planimetered (Lucia Measurement Version 4.6 software), and the ratio between the area stained in blue and the total carotid area was calculated.

Fluorescence-Activated Cell Sorter Analysis
Peripheral blood of rosuvastatin-treated or placebo (normal saline)–treated mice was collected at 1, 10, 11, and 24 days after the initiation of treatment. After lysis of whole blood and Fc blockade (Fc-Block, Pharmingen), the viable lymphocyte population was analyzed for the expression of Sca-1-FITC (clone E13-161.7, Pharmingen) and vascular endothelial growth factor receptor-2 (clone A3, Santa Cruz) conjugated with the corresponding phycoerythrin-labeled secondary antibody (Sigma). Isotype-identical antibodies served as controls (Becton Dickinson). Single- and 2-color flow cytometric analyses were performed by using a Becton Dickinson FACScan equipped with an argon ion laser. Data were evaluated by Cellquest software.

Cell Culture
Spleens were mechanically minced, and mononuclear cells were isolated by use of a Ficoll (Biochrom) gradient. Cells (4x106) were seeded into fibronectin (Sigma)–coated 24-well plates in 0.5 mL endothelial basal medium (CellSystems). After 7 days in culture, cells were stained for 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-Ac-LDL, CellSystems) and FITC-labeled lectin (UEA-1, Sigma). At least 3 high-power fields of each well were analyzed. Cells positive for DiI-Ac-LDL and lectin staining were judged to be EPCs and were counted.

Statistical Analysis
Results are presented as mean±SEM. Significance of the difference between 2 measurements was determined by unpaired Student t test, and multiple comparisons were evaluated by the Newman-Keuls multiple comparison test. Values of P<0.05 were considered significant.


*    Results
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Carotid Injury Model
Fourteen days after carotid injury, vessels were harvested and subjected to histological analysis. Figure 1 shows a representative example of highly reproducible neointimal formation in an artery after injury compared with an unaltered carotid artery.



View larger version (107K):
[in this window]
[in a new window]
 
Figure 1. Hematoxylin and eosin (HE) staining of mouse carotid artery. A, Uninjured carotid artery (control). B, Prominent neointimal formation 14 days after arterial injury.

Retrovirus-Mediated Transfer of the GFP Gene Into Hematopoietic Cells
Transduction efficiency into murine myeloid clonogenic progenitors averaged 80% to 90%. Retrovirally transduced hematopoietic colonies expressed high levels of GFP, as determined by direct visualization with phase-contrast and fluorescence microscopy. All myeloid and lymphocytic lineages displayed a 50% to 80% range of GFP labeling, and GFP expression was stable during the entire observation period.

Reendothelialization From the Bone Marrow
Mice with reconstituted GFP bone marrow were subjected to carotid artery injury procedures. Fourteen days after injury, harvested vessels were analyzed by direct fluorescence microscopy to visualize GFP-positive cells. Immunohistochemical localization of antigens in the arterial vasculature was complicated by the presence of complex molecules such as collagen, elastin, cholesterol, and fluorescent lipids that exhibit autofluorescence over a wide spectrum of wavelengths. Figure 2A and 2B shows the contralateral uninjured carotid artery, in which an autofluorescent signal from the elastic fibers but not from GFP-positive cells was detected. In contrast, scanning of the injured artery revealed GFP-positive cells predominantly at the endothelial monolayer (Figure 2C). Light-microscopic control stainings with a peroxidase-conjugated antibody against GFP confirmed that these cells express the GFP protein and were therefore derived from the bone marrow (data not shown). To confirm the commitment of these GFP-positive cells to the endothelial cell lineage, immunohistological analysis with monoclonal antibodies against vWF (Figure 2D) and vascular endothelial cadherin (data not shown) were used, demonstrating that luminal GFP-positive cells represent endothelial cells. Control stainings with Dapi (data not shown) show the spindle-shaped nucleus of endothelial cells.



View larger version (35K):
[in this window]
[in a new window]
 
Figure 2. Fluorescence microscopy of GFP chimeras. A, Contralateral uninjured carotid arteries were negative for GFP-positive cells. B, vWF IgG-isotype control is shown. Note that the elastic laminas show a high unspecific signal (autofluorescence). C and D, Marginal zone of endothelial lesion is shown. Panel C shows bone marrow–derived cell (arrow) at the luminal side of the vessel. Panel D shows bone marrow–derived cell (arrow) positive for the endothelial cell marker vWF (red). Note 2 endothelial cells (*) that are negative for GFP.

The concomitant appearance of GFP and endothelial cell lineage marker indicates that reendothelialization is influenced by bone marrow–derived cells.

The neointima-forming tissue is mainly composed of vascular smooth muscle cells. Direct fluorescence microscopy and additional staining with antibodies against {alpha}-actin (data not shown) revealed that smooth muscle cells within the analyzed vessel segments were not GFP positive and therefore did not stem from the bone marrow. Macrophages and leukocytes were immunohistologically detected with antibodies against CD45 and Mac-3. However, these cells were primarily localized in the connective tissue adjacent to the injured vessel wall and only rarely at the luminal surface (please see online Figure I, available at www.ahajournals.org).

Effect of Rosuvastatin Treatment on EPCs
Mice were treated with rosuvastatin (20 mg/kg body wt per day). Peripheral blood collected after 1, 10, 11, and 24 days was submitted to fluorescence-activated cell sorter analysis to quantify Sca-1/vascular endothelial growth factor receptor 2–positive cells. Representative fluorescence-activated cell sorter analyses of the control group and of the rosuvastatin-treated group are shown in online Figure IIA and IIB (available at www.ahajournals.org).

Statistical analysis showed an increase of EPCs in the treated group to 0.076% of counted cells (213±16% control) after 24 hours and to 0.25% of counted cells (688±105% control) after 10 days in the peripheral circulation compared with the placebo group (0.036% of counted cells, Figure 3A). Spleens were harvested at 1, 10, 11, and 24 days after the initiation of rosuvastatin treatment, and 4x106 spleen-derived mononuclear cells were seeded in each well. After an in vitro expansion period of 7 days, DiI-Ac-LDL–positive and lectin-positive endothelial cells were quantified as depicted in Figure 3B. A 1-day treatment with rosuvastatin caused an increase to 12 090 endothelial cells (179±34% control) compared with placebo treatment (5995 cells). Further increases were ascertained after 10 and 11 days; however, the enhancing effect of rosuvastatin was more sustained, with a maximum of 54 380 cells after 24 days (454±72% control).



View larger version (13K):
[in this window]
[in a new window]
 
Figure 3. A, Statistical analysis shows an early increase in circulating EPCs in peripheral blood. B, Cell culture experiments reveal a late increase of spleen-derived EPCs after rosuvastatin treatment. Values are mean±SEM. *P<0.05 (n=3 per group).

Rosuvastatin Enhances Reendothelialization From the Bone Marrow
Mice were treated with either placebo or rosuvastatin (20 mg/kg body wt per day) for 10 days before carotid injury. Vessels were harvested 14 days later and evaluated. Rosuvastatin treatment profoundly increased the reendothelialization process, as shown in Figure 4A and 4B. GFP- and vWF-positive cells were abundant at the luminal side of the lesion, indicating accelerated reendothelialization. A semiquantitative analysis of GFP- and vWF-positive cells in relation to the total number of GFP-negative endothelial cells indicated a significant increase in bone marrow–derived endothelial cells committed to reendothelialization after vascular injury (Figure 5A). Thus, the rosuvastatin-induced increase in EPCs is associated with an increased arrival and attachment of bone marrow–derived cells at the site of injury and accelerates endothelial repair mechanisms.



View larger version (10K):
[in this window]
[in a new window]
 
Figure 4. Representative section after rosuvastatin treatment with increased number of bone marrow–derived endothelial cells in the marginal zone of endothelial lesion. GFP-positive endothelial cells (arrows, A) are shown with the corresponding vWF staining (B).



View larger version (31K):
[in this window]
[in a new window]
 
Figure 5. Analyses of injured mouse carotid artery. A, Rosuvastatin increases the number of bone marrow–derived endothelial cells (ECs) in areas of endothelial lesion. Cells with double staining for GFP and vWF were defined as positive and were related to the total number of ECs observed in injured sections of the vessel (control group, n=5, 45 sections; rosuvastatin group, n=4, 60 sections). Values are mean±SEM. *P<0.05. B, Evans blue staining is shown at 1, 7, and 24 days after carotid injury. Reendothelialization was significantly improved after a 7-day treatment with rosuvastatin. C, Neointimal area is significantly reduced after rosuvastatin treatment. Values are mean±SEM. *P<0.05 vs carotid injury (n=5 per group). D, Lumen circumference is significantly increased in mice treated with rosuvastatin compared with control groups.

Rosuvastatin Decreases Neointimal Formation
Because rapid reendothelialization is thought to inhibit neointimal formation,26 we investigated whether the observed rosuvastatin-induced increase of bone marrow–derived endothelial reconstitution results in increased reendothelialization and diminished neointimal formation. Figure 5B demonstrates accelerated reendothelialization in animals after a 7-day treatment with rosuvastatin compared with placebo-treated animals. Rosuvastatin therapy almost completely prevented the development of intimal hyperplasia, suggesting that the bone marrow–driven rapid reendothelialization with rosuvastatin was associated with reduced neointimal formation (Figure 5C and 5D).


*    Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
An intact endothelial monolayer is essential for the physiological functioning of the vasculature.27 Metabolic conditions, such as hypercholesterolemia and diabetes, cause endothelial dysfunction. Mechanical manipulations, such as angioplasty, lead to endothelial denudation.28 Endothelial dysfunction and denudation are both associated with neointimal formation, resulting in narrowing and, ultimately, in occlusion of the diseased vessel.5,6 Improvement of endothelial function and accelerated reendothelialization reduce neointimal formation.5,27 This is of special interest regarding the prevention of restenosis after angioplasty.29 In the past, repair of endothelial cell damage was thought to rely on the outspreading of cells from the adjacent intact vascular wall.7 Recent studies have raised the possibility that bone marrow–derived cells contribute to neoangiogenesis after vascular occlusion and possibly to myocardial regeneration after infarction. In addition, circulating bone marrow–derived cells resembling immature vascular smooth muscle cells seem to contribute to neointimal formation after severe damage of the vessel wall.30 Therefore, stem cell–based intervention could be the basis of novel treatment methods.8,10,1221 Despite these intriguing findings, little is known about the role of the bone marrow in the setting of reendothelialization. Our data indicate that bone marrow–derived cells are directed to vascular lesion sites to reestablish an intact endothelial layer. These cells, characterized by surface markers of immaturity, circulate in the peripheral blood and are capable of adhering to the injured vascular wall. Obviously, the physiological numbers and features of these cells are insufficient to overcome exogenously applied vessel damage, because the unwanted and deleterious neointimal formation occurs reproducibly. Therefore, it may be beneficial to increase the numbers and enhance the attachment of bone marrow–derived progenitor cells to accelerate reendothelialization. Vascularly derived growth factors as well as HMG CoA reductase inhibitors (statins) have been shown to increase the number of circulating premature endothelial cells in mice and humans.22,23,31 Interestingly, the pool of EPCs seems to be dependent on coronary risk factors and coronary heart disease, with decreasing numbers in the peripheral blood associated with an increased risk profile.32 Statins have been shown to produce a decrease in cardiovascular event rates, an effect that is often assumed to be related to their lipid-lowering properties.3335 However, there is evidence that so-called pleiotropic effects, independent of lipid lowering, could account, at least partially, for some of the beneficial clinical effects.36 In the case of enhanced release of EPCs, the activation of phosphatidylinositol 3-kinase–dependent and Akt-dependent pathways seem to be involved.22,31 In the mouse model in the present study, rosuvastatin treatment not only enhanced the number of circulating EPCs but also profoundly enhanced reendothelialization due to attachment of circulating bone marrow–derived cells. This novel finding clearly extends the presently established knowledge regarding bone marrow–derived vascular cells and the reendothelialization processes. Moreover, it suggests that the known advantages of statin treatment may be partially caused by a beneficial influence on bone marrow–derived progenitor cells. However, several questions remain unanswered and warrant further investigation: How are EPCs released in greater quantities by statin treatment? Is this release caused by enhanced proliferation and differentiation of committed stem cells within the bone marrow, or is it due to an increased release of a preexisting pool? What are the exact mechanisms governing these events? What makes endothelial cells attach to the injured vessel wall? Are there inducible adhesion molecules at the site of injury, or are there integrin-like structures on the endothelial cells, or do both occur, propagating the interaction of endothelial cells with the vascular wall? How is this modulated by statins?

These results provide novel insight into the biology of vascular lesion repair. In contrast to widely believed dogma, repair of endothelial cell damage is modulated not only by adjacent vessel structures but also by bone marrow–derived cells. As well as adding another facet to the properties of HMG CoA reductase inhibitors, this discovery raises the possibility that treatment regimens involving bone marrow–derived cells might help prevent advanced vascular lesion formation.


*    Acknowledgments
 
Rosuvastatin was generously provided by AstraZeneca. We thank S. Karren and S. Karl for excellent technical assistance and J. Schultze for assistance with the carotid artery injury model.


*    Footnotes
 
*These authors contributed equally to the present study. Back

Received July 16, 2002; accepted August 21, 2002.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMethods
up arrowResults
up arrowDiscussion
*References
 
1. Lusis AJ. Atherosclerosis. Nature. 2000; 407: 233–241.[CrossRef][Medline] [Order article via Infotrieve]

2. Schwartz SM. Perspectives series: cell adhesion in vascular biology: smooth muscle migration in atherosclerosis and restenosis. J Clin Invest. 1997; 99: 2814–2816.[Medline] [Order article via Infotrieve]

3. Ferns GA, Avades TY. The mechanisms of coronary restenosis: insights from experimental models. Int J Exp Pathol. 2000; 81: 63–88.[CrossRef][Medline] [Order article via Infotrieve]

4. Andres V. Control of vascular smooth muscle cell growth and its implication in atherosclerosis and restenosis. Int J Mol Med. 1998; 2: 81–89.[Medline] [Order article via Infotrieve]

5. Bauters C, Isner JM. The biology of restenosis. Prog Cardiovasc Dis. 1997; 40: 107–116.[CrossRef][Medline] [Order article via Infotrieve]

6. Libby P, Schwartz D, Brogi E, Tanaka H, Clinton SK. A cascade model for restenosis: a special case of atherosclerosis progression. Circulation. 1992; 86 (suppl III): III-47–III-52.[Medline] [Order article via Infotrieve]

7. Carmeliet P, Moons L, Stassen JM, De Mol M, Bouche A, van den Oord JJ, Kock M, Collen D. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am J Pathol. 1997; 150: 761–776.[Abstract]

8. Asahara T, Murohara T, Sullivan A, Silver M, van der ZR, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275: 964–967.[Abstract/Free Full Text]

9. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85: 221–228.[Abstract/Free Full Text]

10. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci. 2001; 938: 221–229.[Medline] [Order article via Infotrieve]

11. Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, Girardi L, Yurt R, Himel H, Rafii S. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res. 2001; 88: 167–174.[Abstract/Free Full Text]

12. Crosby JR, Kaminski WE, Schatteman G, Martin PJ, Raines EW, Seifert RA, Bowen-Pope DF. Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. Circ Res. 2000; 87: 728–730.[Abstract/Free Full Text]

13. Ikenaga S, Hamano K, Nishida M, Kobayashi T, Li TS, Kobayashi S, Matsuzaki M, Zempo N, Esato K. Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model. J Surg Res. 2001; 96: 277–283.[CrossRef][Medline] [Order article via Infotrieve]

14. Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000; 97: 3422–3427.[Abstract/Free Full Text]

15. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver M, Ma H, Kearney M, Isner JM, Asahara T. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103: 634–637.[Abstract/Free Full Text]

16. Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001; 103: 2776–2779.[Abstract/Free Full Text]

17. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001; 107: 1395–1402.[CrossRef][Medline] [Order article via Infotrieve]

18. Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001; 104: 1046–1052.[Abstract/Free Full Text]

19. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.[CrossRef][Medline] [Order article via Infotrieve]

20. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A. 2001; 98: 10344–10349.[Abstract/Free Full Text]

21. Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, Jia ZQ. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999; 100 (suppl II): II-247–II-256.[Medline] [Order article via Infotrieve]

22. Llevadot J, Murasawa S, Kureishi Y, Uchida S, Masuda H, Kawamoto A, Walsh K, Isner JM, Asahara T. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. J Clin Invest. 2001; 108: 399–405.[CrossRef][Medline] [Order article via Infotrieve]

23. Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, Zeiher AM, Dimmeler S. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001; 103: 2885–2890.[Abstract/Free Full Text]

24. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med. 2001; 7: 1356–1361.[CrossRef][Medline] [Order article via Infotrieve]

25. Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol. 2001; 155: 733–738.[Abstract/Free Full Text]

26. Lindner V, Fingerle J, Reidy MA. Mouse model of arterial injury. Circ Res. 1993; 73: 792–796.[Abstract/Free Full Text]

27. Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001; 12: 383–389.[CrossRef][Medline] [Order article via Infotrieve]

28. Libby P, Aikawa M, Kinlay S, Selwyn A, Ganz P. Lipid lowering improves endothelial functions. Int J Cardiol. 2000; 74: S3–S10.[CrossRef][Medline] [Order article via Infotrieve]

29. Nikol S, Huehns TY, Hofling B. Molecular biology and post-angioplasty restenosis. Atherosclerosis. 1996; 123: 17–31.[CrossRef][Medline] [Order article via Infotrieve]

30. Han CI, Campbell GR, Campbell JH. Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res. 2001; 38: 113–119.[CrossRef][Medline] [Order article via Infotrieve]

31. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001; 108: 391–397.[CrossRef][Medline] [Order article via Infotrieve]

32. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001; 89: E1–E7.[Medline] [Order article via Infotrieve]

33. Scandinavian Simvastatin Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344: 1383–1389.[CrossRef][Medline] [Order article via Infotrieve]

34. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995; 333: 1301–1307.[Abstract/Free Full Text]

35. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339: 1349–1357.[Abstract/Free Full Text]

36. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation. 2000; 101: 207–213.[Abstract/Free Full Text]




This article has been cited by other articles:


Home page
Cardiovasc ResHome page
P. Muller, A. Kazakov, P. Jagoda, A. Semenov, M. Bohm, and U. Laufs
ACE inhibition promotes upregulation of endothelial progenitor cells and neoangiogenesis in cardiac pressure overload
Cardiovasc Res, July 1, 2009; 83(1): 106 - 114.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
S.-H. Wang, S.-J. Lin, Y.-H. Chen, F.-Y. Lin, J.-C. Shih, C.-C. Wu, H.-L. Wu, and Y.-L. Chen
Late Outgrowth Endothelial Cells Derived From Wharton Jelly in Human Umbilical Cord Reduce Neointimal Formation After Vascular Injury: Involvement of Pigment Epithelium-Derived Factor
Arterioscler. Thromb. Vasc. Biol., June 1, 2009; 29(6): 816 - 822.
[Abstract] [Full Text] [PDF]


Home page
Vasc MedHome page
D. P Sieveking and M. K. Ng
Cell therapies for therapeutic angiogenesis: back to the bench
Vascular Medicine, May 1, 2009; 14(2): 153 - 166.
[Abstract] [PDF]


Home page
J CARDIOVASC PHARMACOL THERHome page
M. Pirro, G. Schillaci, P. F. Romagno, M. R. Mannarino, F. Bagaglia, R. Razzi, L. Pasqualini, G. Vaudo, and E. Mannarino
Influence of Short-term Rosuvastatin Therapy on Endothelial Progenitor Cells and Endothelial Function
Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2009; 14(1): 14 - 21.
[Abstract] [PDF]


Home page
Circ. Res.Home page
J. B.K. Schwarz, N. Langwieser, N. N. Langwieser, M. J. Bek, S. Seidl, H.-H. Eckstein, B. Lu, A. Schomig, H. Pavenstadt, and D. Zohlnhofer
Novel Role of the CXC Chemokine Receptor 3 in Inflammatory Response to Arterial Injury: Involvement of mTORC1
Circ. Res., January 30, 2009; 104(2): 189 - 200.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
Y. Feng, M. van Eck, E. Van Craeyveld, F. Jacobs, V. Carlier, S. Van Linthout, M. Erdel, M. Tjwa, and B. De Geest
Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer
Blood, January 15, 2009; 113(3): 755 - 764.
[Abstract] [Full Text] [PDF]


Home page
J CARDIOVASC PHARMACOL THERHome page
M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf
An Overview of the Extra-Lipid Effects of Rosuvastatin
Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 157 - 174.
[Abstract] [PDF]


Home page
Ther Adv Cardiovasc DisHome page
T. J. Povsic and P. J. Goldschmidt-Clermont
Review: Endothelial progenitor cells: markers of vascular reparative capacity
Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 199 - 213.
[Abstract] [PDF]


Home page
CirculationHome page
F. Custodis, M. Baumhakel, N. Schlimmer, F. List, C. Gensch, M. Bohm, and U. Laufs
Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E-Deficient Mice
Circulation, May 6, 2008; 117(18): 2377 - 2387.
[Abstract] [Full Text] [PDF]


Home page
Stem CellsHome page
H. Shao, Y. Tan, D. Eton, Z. Yang, M. G. Uberti, S. Li, A. Schulick, and H. Yu
Statin and Stromal Cell-Derived Factor-1 Additively Promote Angiogenesis by Enhancement of Progenitor Cells Incorporation into New Vessels
Stem Cells, May 1, 2008; 26(5): 1376 - 1384.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
G. Foteinos, Y. Hu, Q. Xiao, B. Metzler, and Q. Xu
Rapid Endothelial Turnover in Atherosclerosis-Prone Areas Coincides With Stem Cell Repair in Apolipoprotein E-Deficient Mice
Circulation, April 8, 2008; 117(14): 1856 - 1863.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
P. Muller, A. Kazakov, A. Semenov, M. Bohm, and U. Laufs
Pressure-induced cardiac overload induces upregulation of endothelial and myocardial progenitor cells
Cardiovasc Res, January 1, 2008; 77(1): 151 - 159.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Endocrinol. Metab.Home page
S. Brunner, H. D. Theiss, A. Murr, T. Negele, and W.-M. Franz
Primary hyperparathyroidism is associated with increased circulating bone marrow-derived progenitor cells
Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1670 - E1675.
[Abstract] [Full Text] [PDF]


Home page
DiabetesHome page
C. Werner, C. H. Kamani, C. Gensch, M. Bohm, and U. Laufs
The Peroxisome Proliferator Activated Receptor-{gamma} Agonist Pioglitazone Increases Number and Function of Endothelial Progenitor Cells in Patients With Coronary Artery Disease and Normal Glucose Tolerance
Diabetes, October 1, 2007; 56(10): 2609 - 2615.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
Y. Wang, Y. Zheng, W. Zhang, H. Yu, K. Lou, Y. Zhang, Q. Qin, B. Zhao, Y. Yang, and R. Hui
Polymorphisms of KDR Gene Are Associated With Coronary Heart Disease
J. Am. Coll. Cardiol., August 21, 2007; 50(8): 760 - 767.
[Abstract] [Full Text] [PDF]


Home page
NeuroscientistHome page
M. Cimino, P. Gelosa, A. Gianella, E. Nobili, E. Tremoli, and L. Sironi
Statins: Multiple Mechanisms of Action in the Ischemic Brain
Neuroscientist, June 1, 2007; 13(3): 208 - 213.
[Abstract] [PDF]


Home page
Circ. Res.Home page
V. L.T. Ballard and J. M. Edelberg
Stem Cells and the Regeneration of the Aging Cardiovascular System
Circ. Res., April 27, 2007; 100(8): 1116 - 1127.
[Abstract] [Full Text] [PDF]


Home page
J. Appl. Physiol.Home page
G. L. Hoetzer, G. P. Van Guilder, H. M. Irmiger, R. S. Keith, B. L. Stauffer, and C. A. DeSouza
Aging, exercise, and endothelial progenitor cell clonogenic and migratory capacity in men
J Appl Physiol, March 1, 2007; 102(3): 847 - 852.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
S. Wassmann, N. Werner, T. Czech, and G. Nickenig
Improvement of Endothelial Function by Systemic Transfusion of Vascular Progenitor Cells
Circ. Res., October 13, 2006; 99(8): E74 - E83.
[Abstract] [Full Text] [PDF]


Home page
JCBHome page
L. Zeng, Q. Xiao, A. Margariti, Z. Zhang, A. Zampetaki, S. Patel, M. C. Capogrossi, Y. Hu, and Q. Xu
HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells
J. Cell Biol., September 25, 2006; 174(7): 1059 - 1069.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart JHome page
M. Baumhakel, N. Werner, M. Bohm, and G. Nickenig
Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease
Eur. Heart J., September 2, 2006; 27(18): 2184 - 2188.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Respir. Cell Mol. Bio.Home page
G. P. Fadini, A. Avogaro, and C. Agostini
Pathophysiology of circulating progenitor cells in pulmonary disease and parallels with cardiovascular disease.
Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 403 - 404.
[Full Text] [PDF]


Home page
JEMHome page
S. Massberg, I. Konrad, K. Schurzinger, M. Lorenz, S. Schneider, D. Zohlnhoefer, K. Hoppe, M. Schiemann, E. Kennerknecht, S. Sauer, et al.
Platelets secrete stromal cell-derived factor 1{alpha} and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo
J. Exp. Med., May 15, 2006; 203(5): 1221 - 1233.
[Abstract] [Full Text] [PDF]


Home page
J Am Coll CardiolHome page
R. Blindt, F. Vogt, I. Astafieva, C. Fach, M. Hristov, N. Krott, B. Seitz, A. Kapurniotu, C. Kwok, M. Dewor, et al.
A Novel Drug-Eluting Stent Coated With an Integrin-Binding Cyclic Arg-Gly-Asp Peptide Inhibits Neointimal Hyperplasia by Recruiting Endothelial Progenitor Cells
J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1786 - 1795.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
C. Tso, G. Martinic, W.-H. Fan, C. Rogers, K.-A. Rye, and P. J. Barter
High-Density Lipoproteins Enhance Progenitor-Mediated Endothelium Repair in Mice
Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1144 - 1149.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
T. Thum, D. Fraccarollo, P. Galuppo, D. Tsikas, S. Frantz, G. Ertl, and J. Bauersachs
Bone marrow molecular alterations after myocardial infarction: Impact on endothelial progenitor cells
Cardiovasc Res, April 1, 2006; 70(1): 50 - 60.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
M. Ii, H. Takenaka, J. Asai, K. Ibusuki, Y. Mizukami, K. Maruyama, Y.-s. Yoon, A. Wecker, C. Luedemann, E. Eaton, et al.
Endothelial Progenitor Thrombospondin-1 Mediates Diabetes-Induced Delay in Reendothelialization Following Arterial Injury
Circ. Res., March 17, 2006; 98(5): 697 - 704.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Respir. Cell Mol. Bio.Home page
V. I. Peinado, J. Ramirez, J. Roca, R. Rodriguez-Roisin, and J. A. Barbera
Identification of Vascular Progenitor Cells in Pulmonary Arteries of Patients with Chronic Obstructive Pulmonary Disease
Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 257 - 263.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
E. B. Friedrich, K. Walenta, J. Scharlau, G. Nickenig, and N. Werner
CD34-/CD133+/VEGFR-2+ Endothelial Progenitor Cell Subpopulation With Potent Vasoregenerative Capacities
Circ. Res., February 17, 2006; 98(3): e20 - e25.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
N. Werner and G. Nickenig
Influence of Cardiovascular Risk Factors on Endothelial Progenitor Cells: Limitations for Therapy?
Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 257 - 266.
[Abstract] [Full Text] [PDF]


Home page
J. Neurosci.Home page
A. K. Stalder, F. Ermini, L. Bondolfi, W. Krenger, G. J. Burbach, T. Deller, J. Coomaraswamy, M. Staufenbiel, R. Landmann, and M. Jucker
Invasion of Hematopoietic Cells into the Brain of Amyloid Precursor Protein Transgenic Mice
J. Neurosci., November 30, 2005; 25(48): 11125 - 11132.
[Abstract] [Full Text] [PDF]


Home page
NEJMHome page
N. Werner, S. Kosiol, T. Schiegl, P. Ahlers, K. Walenta, A. Link, M. Bohm, and G. Nickenig
Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes
N. Engl. J. Med., September 8, 2005; 353(10): 999 - 1007.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al.
Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans
Circulation, May 10, 2005; 111(18): 2356 - 2363.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
M. Simons
Angiogenesis: Where Do We Stand Now?
Circulation, March 29, 2005; 111(12): 1556 - 1566.
[Full Text] [PDF]


Home page
Circ. Res.Home page
F. Blaschke, O. Leppanen, Y. Takata, E. Caglayan, J. Liu, M. C. Fishbein, K. Kappert, K. I. Nakayama, A. R. Collins, E. Fleck, et al.
Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries
Circ. Res., December 10, 2004; 95(12): e110 - e123.
[Abstract] [Full Text] [PDF]


Home page
BloodHome page
J. Chou, N. Mackman, G. Merrill-Skoloff, B. Pedersen, B. C. Furie, and B. Furie
Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation
Blood, November 15, 2004; 104(10): 3190 - 3197.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
M. Abedin, Y. Tintut, and L. L. Demer
Mesenchymal Stem Cells and the Artery Wall
Circ. Res., October 1, 2004; 95(7): 671 - 676.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
L. G. Melo, M. Gnecchi, A. S. Pachori, D. Kong, K. Wang, X. Liu, R. E. Pratt, and V. J. Dzau
Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease
Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1761 - 1774.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
E. A. Liehn, A. Schober, and C. Weber
Blockade of Keratinocyte-Derived Chemokine Inhibits Endothelial Recovery and Enhances Plaque Formation After Arterial Injury in ApoE-Deficient Mice
Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1891 - 1896.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
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]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
C. Zhang, J. Yang, and L. K. Jennings
Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery
Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H659 - H666.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
U. Landmesser, B. Hornig, and H. Drexler
Endothelial Function: A Critical Determinant in Atherosclerosis?
Circulation, June 1, 2004; 109(21_suppl_1): II-27 - II-33.
[Abstract] [Full Text] [PDF]


Home page
Eur Heart J SupplHome page
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]


Home page
CirculationHome page
U. Laufs, N. Werner, A. Link, M. Endres, S. Wassmann, K. Jurgens, E. Miche, M. Bohm, and G. Nickenig
Physical Training Increases Endothelial Progenitor Cells, Inhibits Neointima Formation, and Enhances Angiogenesis
Circulation, January 20, 2004; 109(2): 220 - 226.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
A. Iwakura, C. Luedemann, S. Shastry, A. Hanley, M. Kearney, R. Aikawa, J. M. Isner, T. Asahara, and D. W. Losordo
Estrogen-Mediated, Endothelial Nitric Oxide Synthase-Dependent Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury
Circulation, December 23, 2003; 108(25): 3115 - 3121.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
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]


Home page
Circ. Res.Home page
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]


Home page
CirculationHome page
R. Gulati, D. Jevremovic, T. E. Peterson, T. A. Witt, L. S. Kleppe, C. S. Mueske, A. Lerman, R. G. Vile, and R. D. Simari
Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury
Circulation, September 23, 2003; 108(12): 1520 - 1526.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
N. Werner, S. Junk, U. Laufs, A. Link, K. Walenta, M. Bohm, and G. Nickenig
Intravenous Transfusion of Endothelial Progenitor Cells Reduces Neointima Formation After Vascular Injury
Circ. Res., July 25, 2003; 93 (2): e17 - e24.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
M. Hristov, W. Erl, and P. C. Weber
Endothelial Progenitor Cells: Mobilization, Differentiation, and Homing
Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1185 - 1189.
[Abstract] [Full Text] [PDF]


Home page
CirculationHome page
P. E. Szmitko, P. W.M. Fedak, R. D. Weisel, D. J. Stewart, M. J.B. Kutryk, and S. Verma
Endothelial Progenitor Cells: New Hope for a Broken Heart
Circulation, June 24, 2003; 107(24): 3093 - 3100.
[Full Text] [PDF]


Home page
CirculationHome page
K. Strehlow, N. Werner, J. Berweiler, A. Link, U. Dirnagl, J. Priller, K. Laufs, L. Ghaeni, M. Milosevic, M. Bohm, et al.
Estrogen Increases Bone Marrow-Derived Endothelial Progenitor Cell Production and Diminishes Neointima Formation
Circulation, June 24, 2003; 107(24): 3059 - 3065.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
U. Laufs and J. K. Liao
Rapid Effects of Statins: From Prophylaxis to Therapy for Ischemic Stroke
Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 156 - 157.
[Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
G. P. van Nieuw Amerongen, P. Koolwijk, A. Versteilen, and V. W.M. van Hinsbergh
Involvement of RhoA/Rho Kinase Signaling in VEGF-Induced Endothelial Cell Migration and Angiogenesis In Vitro
Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 211 - 217.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
J. Thyberg
Re-endothelialization Via Bone Marrow-Derived Progenitor Cells: Still Another Target of Statins in Vascular Disease
Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1509 - 1511.
[Full Text] [PDF]


This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Data Supplement
Right arrow All Versions of this Article:
22/10/1567    most recent
01.ATV.0000036417.43987.D8v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Werner, N.
Right arrow Articles by Nickenig, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Werner, N.
Right arrow Articles by Nickenig, G.
Related Collections
Right arrow Health policy and outcome research
Right arrow Other Ethics and Policy
Right arrow Cardiovascular imaging agents/Techniques
Right arrow Coagulation and fibronolysis