Published online before print March 2, 2006, doi: 10.1161/01.ATV.0000215982.14003.b7
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Vascular Biology |
Plasminogen Activator Inhibitor-1 From Bone Marrow–Derived Cells Suppresses Neointimal Formation After Vascular Injury in Mice
From the Department of Cardiology and Pulmonology (K.S., M.R.S., C.D., M.P., G.H., S.V.K.), Georg August University School of Medicine, Goettingen, Germany; and Department of Radiotherapy and Radiooncology (M.N., E.W.), Georg August University School of Medicine, Goettingen, Germany.
Correspondence to Katrin Schäfer, MD, Associate Professor of Medicine, Department of Cardiology and Pulmonology, Georg August University School of Medicine, D-37099 Goettingen, Germany. E-mail kschaefer{at}med.uni-goettingen.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Objective— To investigate the ability of bone marrow (BM)–derived cells to modulate neointimal growth after injury by expressing plasminogen activator inhibitor-1 (PAI-1).
Methods and Results— We performed BM transplantation (BMT) in lethally irradiated wild-type (WT) and PAI-1–/– mice. Three weeks after carotid injury with ferric chloride, analysis of Y-chromosome DNA expression in the vessel wall of female hosts revealed that 20.8±6.0% of the cells in the neointima and 37.6±5.7% of those in the media were of BM origin. Lack of PAI-1 in either the host or the donor cells did not affect recruitment of BM-derived cells into sites of vascular injury. The neointima consisted predominantly of smooth muscle cells, and a proportion of these cells expressed PAI-1. Overall, lack of PAI-1 was associated with enhanced neointimal formation. However, importantly, BMTWT
PAI-1–/– mice exhibited reduced neointimal area (P=0.05) and luminal stenosis (P=0.04) compared with BMTPAI-1–/–PAI-1–/– mice. Although PAI-1–expressing cells were shown to be present in BMTWTPAI-1–/– lesions, these mice did not exhibit detectable levels of the inhibitor in the circulation, suggesting that local production of PAI-1 by cells in the neointima and media was sufficient to reduce luminal stenosis.
Conclusions— PAI-1 from BM-derived cells appears capable of suppressing neointimal growth after vascular injury.
We performed whole-body irradiation and bone marrow transplantation experiments followed by carotid artery injury with ferric chloride in mice. Our results support the ability of bone marrow–derived cells to modulate neointimal growth after injury, which appears to be partly mediated by the expression of plasminogen activator inhibitor-1
Key Words: bone marrow–derived vascular progenitor cells • mouse model • plasminogen activator inhibitor • vascular injury
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Recent evidence suggests that the vascular wound healing response to injury may involve not only the migration of local smooth muscle cells (SMCs) from neighboring "healthy" tissue but also the recruitment of circulating vascular progenitor cells from the bone marrow (BM) into the vessel wall.1–3 The mechanisms by which BM-derived SMCs modulate neointimal growth remain largely unknown, but we hypothesized that plasminogen activator inhibitor-1 (PAI-1) could be one of the mediators of this process. In fact, PAI-1 is expressed by vascular endothelial and SMCs,4 and its expression is upregulated in human atherosclerotic lesions5 and during the vascular wound healing response to experimental injury.6 Previous studies that attempted to clarify the role of PAI-1 in neointimal formation using various models of arterial injury in gene-inactivated mice yielded rather contradicting findings,7–11 but the apparent discrepancies need to be interpreted in the context of the pleiotropic effects of the inhibitor on vascular cells and the surrounding matrix.12 For example, PAI-1 stabilizes arterial thrombi in vivo6 and may thus have provided a provisional matrix facilitating cell migration, at least in injury models characterized by heavy deposition of fibrin.8 However, under different experimental conditions,7,11 PAI-1 expression in the vessel wall may have contributed to reduced cell motility by inhibiting both pericellular plasmin-mediated proteolysis and the attachment of migrating cells to the extracellular matrix via integrins and the urokinase receptor.12
See cover and page 1196
In the present study, we investigated the possible role of PAI-1 in mediating at least some of the effects of BM-derived cells on vascular remodeling after injury. Whole body irradiation and BM transplantation (BMT) experiments were performed in wild-type (WT) and PAI-1–deficient mice (Jackson Laboratories, Bar Harbor, Me), followed by induction of arterial injury using the ferric chloride injury model.6,13,14 Apart from quantitatively assessing and characterizing the BM-derived cells involved in the remodeling process, we examined their ability to express PAI-1 and sought to determine whether the expression of the inhibitor by cells of BM origin might help modulate (ie, contain neointimal growth and luminal stenosis in this experimental model of severe damage to the vessel wall).
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The Methods are provided as supplemental online material, available at http://atvb.ahajournals.org.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Irradiation and BMT Does Not Alter the Effects of PAI-1 on Arterial Thrombosis and Neointimal Growth
WT or PAI-1–deficient (PAI-1–/–) mice were lethally irradiated and transplanted with unfractionated WT or PAI-1–/– BM (106 cells). Four weeks after BMT (ie, after allowing for complete BM reconstitution), carotid artery injury was induced using ferric chloride.4,6 The following mouse groups were studied: WT mice transplanted with WT BM (BMTWT
WT; n=8); WT mice that received PAI-1–/– BM (BMTPAI-1–/–WT; n=14); PAI-1–/– mice with PAI-1–/– BM (BMTPAI-1–/–PAI-1–/–; n=12); and PAI-1–/– with WT BM (BMTWTPAI-1–/–; n=12).
We have previously shown that lack of PAI-1 in mice is associated with formation of unstable thrombi and prolongation of the time to thrombotic occlusion after injury.4,6 In the present study, BMTPAI-1–/–PAI-1–/– also tended to have prolonged times to complete occlusion compared with BMTWTWT mice (15.3±1.5 versus 13.2±1.8 minutes), although the difference did not reach statistical significance. The patency rates 25 minutes after injury were 38% in BMTPAI-1–/–PAI-1–/– compared with 12% in BMTWTWT mice (P=0.3). Moreover, the mean time to thrombotic occlusion was almost identical between mice of the BMTWTWT group and a control group of 15 nonirradiated, nontransplanted WT mice (13.2±1.8 versus 13.7±0.9 minutes; P=0.95), supporting the conclusion that irradiation or BMT per se did not appear to affect the thrombotic response of WT and PAI-1–/– mice to arterial injury.
Three weeks after injury, carotid vessels were harvested and the extent of neointimal formation was quantitatively assessed.4 Lack of PAI-1 was associated with enhanced neointimal formation after injury (representative findings shown in Figure I, available online at http://atvb.ahajournals.org). Overall, the neointimal area was larger in BMTPAI-1–/–PAI-1–/– compared with BMTWTWT mice (5525±852 versus 2907±493 µm2; P=0.04), and luminal stenosis increased from 5.7±1.0% in BMTWTWT to 13.6±2.3% in BMTPAI-1–/–PAI-1–/– mice (P=0.02; results summarized in Figure II, available online at http://atvb.ahajournals.org). Of note, these differences were similar to those observed between nonirradiated, nontransplanted WT (n=9) and PAI-1–/– (n=13) controls. In these latter studies, neointimal area was 4865±1173 µm2 in WT mice compared with 8084±1096 µm2 in their PAI-1–/– counterparts (P=0.06), and luminal stenosis 7.0±1.0% versus 14.9±2.7% (P=0.03). Thus, PAI-1 suppressed neointimal growth after ferric chloride–induced injury. Our data further suggest that whole body irradiation slightly (but not significantly) reduced neointimal growth and luminal stenosis both in WT and in PAI-1–/– mice.
Presence of BM-Derived Cells in the Vessel Wall
Recent evidence suggests that BM-derived vascular progenitor cells participate to a varying extent in the wound healing response after mechanical injury of mouse arteries.1,15 To assess the presence of these cells in the neointima in the ferric chloride injury model, 2 different approaches were used. First, female animals were irradiated and transplanted with unfractionated BM harvested from the tibia and femur of male mice. After BM reconstitution and 3 weeks after injury, BM-derived (male) cells in the vessel wall were detected using in situ hybridization for Y-chromosome DNA. Second, BM from ß-galactosidase transgenic (ROSA26) mice was transplanted into irradiated LacZ-WT mice. BM-derived cells in the vessel wall were identified using 5-bromo-4-chloro-3-indolyl ß-D-galactoside (X-gal) as a substrate for detection of ß-galactosidase enzyme activity. As shown in Figure 1, BM-derived cells could be found in the neointima (Figure 1a and 1b) and media (Figure 1c and 1d) but also in the adventitia, where they were shown to line perivascular small blood vessels (Figure 1e and 1f). Quantitative analysis of Y-chromosome–positive and LacZ-positive cells showed that the 2 methods yielded comparable results and a similar proportion of BM-derived cells in the vessel wall (Table). Of note, neither method detected donor (Y-DNA– or LacZ-positive) cells in uninjured carotid arteries (Figure 1g).
|
|
Spatial and Temporal Distribution of BM-Derived Cells
Analysis of serial cross-sections through the injured segment (data not shown) and longitudinal sections (Figure 1h) revealed that the presence of BM-derived cells was most pronounced at the center of the injury and gradually decreased toward its proximal and distal borders. To assess the time course of migration of BM-derived cells into the neointima, additional experiments were performed using BM from ß-galactosidase–transgenic mice. LacZ-positive cells could not be detected in the vessel wall 30 minutes, 24 hours, or 1 week after injury, despite the abundance of BM-derived (LacZ-positive) cells in the vascular lumen (Figure 2a through 2d). In fact, the absence of BM-derived cells coincided with the complete loss of SMCs in the media for up to 1 week after the severe injury induced to the vessel wall by ferric chloride. Thus, migration of circulating BM-derived cells into the vessel wall occurred relatively late during the remodeling process, between the first and the third week after injury.
|
Characterization of Vascular Cells of BM Origin
In accordance with previous observations,6 immunostaining for von Willebrand factor (vWF) and 
-actin confirmed that 3 weeks after injury, the endothelial cell layer had been completely reconstituted, and the neointima consisted predominantly of vascular SMCs. Double staining revealed that vWF+/LacZ+ (endothelial) cells were only occasionally detected (Figure 3a and 3b), whereas a substantial proportion of the LacZ-positive cells in the neointima and media also stained positive for -actin (30.6±5.0%; range 5% to 60%; Figure 3c and 3d) and, to a smaller extent, smooth muscle–myosin heavy chain (Figure 3e). In contrast, Mac3-positive tissue macrophages could be clearly distinguished from LacZ-positive cells within the media (Figure 3f).
|
BM-Derived Cells Express PAI-1 in Vascular Lesions
Immunohistochemical analysis of PAI-1 antigen expression showed that, as opposed to BMTPAI-1–/–PAI-1–/– mice, both BMTWTWT and BMTPAI-1–/–WT mice expressed PAI-1 in the vessel wall 3 weeks after injury (data not shown). The PAI-1–immunopositive area was reduced from 20.5±1.0% in BMTWTWT to 7.3±2.4% in BMTPAI-1–/–WT mice (P<0.001). However, importantly, transplantation of WT BM into PAI-1–/– mice (BMTWTPAI-1–/–) resulted in the presence of PAI-1–expressing cells in the neointima (immunopositive area 6.3±1.1%). PAI-1–positive cells already appeared in the vessel wall 1 week after injury (Figure 2e and 2f), and at 3 weeks, PAI-1 immunoreactivity in lesions correlated significantly with the LacZ-positive area (r=0.78; P=0.022). Using immunofluorescence double labeling of frozen sections, the cells expressing PAI-1 could be identified as CD31- or vWF-positive endothelial cells (Figure 4a and 4b) and -actin–positive (data not shown) or myosin heavy chain–positive SMCs (Figure 4c). Of note, it is unlikely that the PAI-1 detected in the vessel wall had been released from circulating platelets during or after injury because we showed in a previous4 and in the present (Figure III, available online at http://atvb.ahajournals.org) study that, in contrast to human platelets, mouse platelets do not contain detectable amounts of PAI-1. Moreover, measurement of circulating PAI-1 antigen revealed a mean concentration of 3.5±1.1 ng/mL in plasma from BMTWTWT mice, whereas PAI-1 antigen was undetectable not only in BMTPAI-1–/–PAI-1–/– but also in 9 of 10 BMTWTPAI-1–/– mice (mean concentration 0.11±0.11 ng/mL).
|
Finally, our studies revealed that lack of PAI-1 in either the host or the donor did not significantly affect the proportion of BM-derived cells in vascular lesions, as demonstrated by quantitative comparison of Y chromosome–positive donor cells in female recipients of the 4 mouse groups (BMTWTWT, BMTPAI-1–/–WT, BMTPAI-1–/–PAI-1–/–, and BMTWTPAI-1–/–; data not shown).
PAI-1 Expressed By BM-Derived Cells May Suppress Neointimal Formation
We investigated the functional role of BM-derived cells in the neointima and their possible contribution to vascular remodeling in relation to PAI-1 expression. As mentioned above and shown in Figure I, lack of PAI-1 was associated with enhanced neointimal formation after ferric chloride–induced injury. Figure I further shows that neither the neointimal area nor the severity of luminal stenosis was significantly affected in WT mice receiving PAI-1–/– BM compared with BMTWTWT mice (P=0.70 and 0.89, respectively; Figure II). On the other hand, transplantation of PAI-1–expressing (ie, WT BM cells into PAI-1–/–) mice resulted in marked reduction both of neointimal size (3416±595 versus 5525±852 µm2; P=0.05) and the degree of luminal stenosis (7.7±1.4 versus 13.6±2.3%; P=0.04) compared with BMTPAI-1–/–PAI-1–/– mice (Figure I; summarized in Figure II). Thus, PAI-1 expressed by BM-derived cells appeared to be capable of suppressing, at least in part, neointimal growth after arterial injury.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Proliferation and migration of vascular SMCs plays a crucial role in intimal hyperplasia and is a common feature of atherosclerotic lesions. The origin of neointimal SMCs is diverse;16 besides endothelial transdifferentiation17,18 and the migration of dedifferentiated medial SMCs or adventitial myofibroblasts into the neointima,19 it may involve the recruitment of vascular progenitor cells from the BM and the circulation.20,21 In fact, BM-derived progenitor cells have been detected both in human22,23 and in murine1,24 vascular lesions.
In the present study, we examined whether, and to what extent, BM-derived cells participate in the wound healing response to vascular injury. The spatial and temporal pattern of the recruitment of BM-derived cells into the vessel wall was studied, and the functional consequences of this process were investigated, focusing on the role of PAI-1. Based on the demonstration of ß-galactosidase activity in WT mice, or the detection of male (Y-chromosome DNA-positive) donor cells in female mice, we identified 
21% of the cells in the neointima and 37% of the cells in the media as being of BM origin 3 weeks after injury. In our study, Y-DNA in situ hybridization and X-gal staining both yielded similar results, but it has been suggested that the number of Y-DNA–positive cells may be underestimated by in situ hybridization because of the small and eccentric nuclear staining pattern.25 Importantly, several (31%) of the LacZ-positive BM-derived cells also stained positive for -actin, suggesting that they had transdifferentiated into vascular SMCs 3 weeks after injury.
Both the mean proportion of BM-derived cells in the vessel wall and the wide range of values observed in individual mice after ferric chloride injury are in accordance with previous studies that applied various models of mechanically induced arterial injury using LacZ1,3 or green fluorescent protein transgenic15 mice or gender-mismatched BMT.1,26 Together, our results and those of other authors suggest that the type and severity of vascular injury is an important determinant of the extent of progenitor cell recruitment.15 Thus, the relatively high percentage of Y-DNA– or LacZ-positive cells in our studies is consistent with the observation that ferric chloride induces extensive endothelial denudation and medial cell loss over 
1 week.6 Of course, experimental injury models, including the one used in the present study, cannot exactly reproduce the pathophysiology of human atherosclerosis, atherothrombosis, or restenosis. Nevertheless, injury with ferric chloride is characterized by the reproducible formation of platelet-rich arterial thrombi, and the lesions that develop in mice during the remodeling process exhibit histological similarities with human atherosclerotic plaques.6,13
Because our studies were performed in mice that had been lethally irradiated and then reconstituted with unfractionated whole BM, the exact phenotype of the progenitor cells that gave rise to vascular SMCs cannot not be determined. Previous studies suggested that endothelial and mural cells are derived from a common progenitor,27 whereas others suggested the presence of separate progenitors for endothelial and SMCs.28 Vascular progenitor cells appear to reside within the hematopoietic stem cell fraction, and hematopoietic stem cells were shown to differentiate into SMCs after seeding on primary rat aortic SMCs.1 Notably, BM stromal cells also have the potential to differentiate into SMCs.29,30 On the other hand, the non-BM-derived (LacZ-negative or Y-DNA–negative) cells found in neointimal lesions in our study could have originated from dedifferentiation, migration, and proliferation of resident cells in the media or adventitia.19 However, it cannot be excluded that radio-resistant progenitor cells within the vessel wall may also have been involved in the remodeling process.24
Although the present study and previous reports strongly support the recruitment of BM-derived cells into vascular lesions, the functional contribution of these cells to the remodeling process remains controversial to date. To begin to dissect the mechanisms mediating the effects of BM-derived cells in the wall of injured vessels, we examined the potential of BM-derived cells to produce PAI-1 and thus possibly modulate extracellular matrix proteolysis, cell adhesion, and migration. In accordance with a previous model of severe injury to the vessel wall,7 lack of PAI-1 was associated with significantly enhanced neointimal growth and luminal stenosis after ferric chloride injury, and this effect was not altered by irradiation or BMT. Thus, the modulation of neointimal growth by the inhibitor appeared to result predominantly from its direct (inhibitory) effects on cell migration.12 However, a number of studies, some of which yielded contradicting results despite using very similar injury models,7,10,11,31 suggest that the inhibitory effects of PAI-1 on neointimal growth may be neutralized, or even reversed, by its thrombus-stabilizing effects, depending on the severity and the extent of the thrombotic response, which may be highly variable in vivo.32 Notably, the effects of PAI-1 on neointimal growth do not appear to involve modulation of the recruitment of BM-derived cells into sites of vascular injury because we found that lack of PAI-1 in either the host or the donor cells did not affect the proportion of BM-derived cells in the vessel wall.
In support of a role of BM-derived cells in modulating neointimal growth, we found that the increase of neointimal formation in mice lacking PAI-1 was almost completely prevented in the presence of PAI-1–expressing BM-derived cells in the vessel wall. Based on our findings in LacZ chimeras and gender-mismatched mice, and on the detection of PAI-1–immunopositive cells in the vessel wall of PAI-1–deficient host mice, the production of PAI-1 by less than one third of the cells in the neointima and the media appeared sufficient to restore the WT phenotype (ie, suppress neointimal growth and reduce luminal stenosis). It is very unlikely that PAI-1 released from circulating (donor) platelets contributed to these effects because it was shown previously4,33 and in the present study (supplemental data) that PAI-1 protein is undetectable in mouse platelets as opposed to the relatively high PAI-1 levels in human platelets.34 Moreover, our finding that transplantation of WT (ie, PAI-1–expressing) BM cells did not result in detectable levels of the inhibitor in the circulation of PAI-1–/– mice adds further support to the importance of local (vascular) versus systemic PAI-1 for vascular remodeling.
In conclusion, the present study extends previous findings by showing that BM-derived cells are recruited into, and form a substantial component of, vascular lesions developing in mice after injury. Moreover, our results suggest that these cells are capable of regulating cell migration and the vascular remodeling process, and that these effects may be related, at least in part, to the expression of protease inhibitors such as PAI-1. This experimental approach may prove useful for dissecting the mechanisms mediating the (presumed) pleiotropic effects of BM-derived progenitor cells on vascular homeostasis. In addition, the modification of the expression profile of recruited progenitor cells may represent a novel strategy for preventing the restenotic process after arterial injury.
|
Acknowledgments |
|---|
This work was supported by a grant ("Schwerpunktförderung: Stammzellforschung") from the University of Goettingen to K.S. The authors would like to thank Irene Lang, MD, Department of Cardiology, University Hospital Vienna, Austria, for helpful discussions, and Stephanie Minne and Vera Unterstab for assistance with histological analyses.
Received September 24, 2005; accepted February 16, 2006.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8: 403–409.[CrossRef][Medline] [Order article via Infotrieve]
- Xu Y, Arai H, Zhuge X, Sano H, Murayama T, Yoshimoto M, Heike T, Nakahata T, Nishikawa S, Kita T, Yokode M. Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice. Arterioscler Thromb Vasc Biol. 2004; 24: 477–482.
[Abstract/Free Full Text] - 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]
- Schäfer K, Müller K, Hecke A, Mounier E, Goebel J, Loskutoff DJ, Konstantinides S. Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 2003; 23: 2097–2103.
[Abstract/Free Full Text] - Schneiderman J, Sawdey MS, Keeton MR, Bordin GM, Bernstein EF, Dilley RB, Loskutoff DJ. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A. 1992; 89: 6998–7002.
[Abstract/Free Full Text] - Konstantinides S, Schäfer K, Thinnes T, Loskutoff DJ. Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice. Circulation. 2001; 103: 576–583.
[Abstract/Free Full Text] - Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard RD. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation. 1997; 96: 3180–3191.
[Abstract/Free Full Text] - Ploplis VA, Cornelissen I, Sandoval-Cooper MJ, Weeks L, Noria FA, Castellino FJ. Remodeling of the vessel wall after copper-induced injury is highly attenuated in mice with a total deficiency of plasminogen activator inhibitor-1. Am J Pathol. 2001; 158: 107–117.
[Abstract/Free Full Text] - DeYoung MB, Tom C, Dichek DA. Plasminogen activator inhibitor type 1 increases neointima formation in balloon-injured rat carotid arteries. Circulation. 2001; 104: 1972–1971.
[Abstract/Free Full Text] - Peng L, Bhatia N, Parker AC, Zhu Y, Fay WP. Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries. Arterioscler Thromb Vasc Biol. 2002; 22: 934–939.
[Abstract/Free Full Text] - de Waard V, Arkenbout K, Carmeliet P, Lindner V, Pannekoek H. Plasminogen activator inhibitor 1 and vitronectin protect against stenosis in a murine carotid ligation model. Arterioscler Thromb Vasc Biol. 2002; 22: 1978–1983.
[Abstract/Free Full Text] - Konstantinides S, Schäfer K, Loskutoff DJ. Do PAI-1 and vitronectin promote or inhibit neointima formation? The exact role of the fibrinolytic system in vascular remodeling remains uncertain. Arterioscler Thromb Vasc Biol. 2002; 22: 1943–1945.
[Free Full Text] - Schäfer K, Konstantinides S, Riedel C, Thinnes T, Muller K, Dellas C, Hasenfuss G, Loskutoff DJ. Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase- or tissue-type plasminogen activator. Circulation. 2002; 106: 1847–1852.
[Abstract/Free Full Text] - Zhu Y, Farrehi PM, Fay WP. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice. Circulation. 2001; 103: 3105–3110.
[Abstract/Free Full Text] - Tanaka K, Sata M, Hirata Y, Nagai R. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res. 2003; 93: 783–790.
[Abstract/Free Full Text] - Zalewski A, Shi Y, Johnson AG. Diverse origin of intimal cells: smooth muscle cells, myofibroblasts, fibroblasts, and beyond? Circ Res. 2002; 91: 652–655.
[Free Full Text] - Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res. 2002; 90: 1189–1196.
[Abstract/Free Full Text] - DeRuiter MC, Poelmann RE, VanMunsteren JC, Mironov V, Markwald RR, Gittenberger-de Groot AC. Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. Circ Res. 1997; 80: 444–451.
[Abstract/Free Full Text] - Shi Y, O’Brien JE, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation. 1996; 94: 1655–1664.
[Abstract/Free Full Text] - Saiura A, Sata M, Hirata Y, Nagai R, Makuuchi M. Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med. 2001; 7: 382–383.[CrossRef][Medline] [Order article via Infotrieve]
- Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation. 2002; 106: 1199–1204.
[Abstract/Free Full Text] - Glaser R, Lu MM, Narula N, Epstein JA. Smooth muscle cells, but not myocytes, of host origin in transplanted human hearts. Circulation. 2002; 106: 17–19.
[Abstract/Free Full Text] - Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D, Miller DV, Russell SJ, Litzow MR, Edwards WD. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci U S A. 2003; 100: 4754–4759.
[Abstract/Free Full Text] - Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001; 7: 738–741.[CrossRef][Medline] [Order article via Infotrieve]
- Poulsom R, Forbes SJ, Hodivala-Dilke K, Ryan E, Wyles S, Navaratnarasah S, Jeffery R, Hunt T, Alison M, Cook T, Pusey C, Wright NA. Bone marrow contributes to renal parenchymal turnover and regeneration. J Pathol. 2001; 195: 229–235.[CrossRef][Medline] [Order article via Infotrieve]
- Religa P, Bojakowski K, Maksymowicz M, Bojakowska M, Sirsjo A, Gaciong Z, Olszewski W, Hedin U, Thyberg J. Smooth-muscle progenitor cells of bone marrow origin contribute to the development of neointimal thickenings in rat aortic allografts and injured rat carotid arteries. Transplantation. 2002; 74: 1310–1315.[Medline] [Order article via Infotrieve]
- Yamashita J, Itoh H, Hirashima M, Ogawa M, Nishikawa S, Yurugi T, Naito M, Nakao K, Nishikawa S. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature. 2000; 408: 92–96.[CrossRef][Medline] [Order article via Infotrieve]
- Majka SM, Jackson KA, Kienstra KA, Majesky MW, Goodell MA, Hirschi KK. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J Clin Invest. 2003; 111: 71–79.[CrossRef][Medline] [Order article via Infotrieve]
- Kashiwakura Y, Katoh Y, Tamayose K, Konishi H, Takaya N, Yuhara S, Yamada M, Sugimoto K, Daida H. Isolation of bone marrow stromal cell-derived smooth muscle cells by a human SM22alpha promoter: in vitro differentiation of putative smooth muscle progenitor cells of bone marrow. Circulation. 2003; 107: 2078–2081.
[Abstract/Free Full Text] - Kobayashi N, Yasu T, Ueba H, Sata M, Hashimoto S, Kuroki M, Saito M, Kawakami M. Mechanical stress promotes the expression of smooth muscle-like properties in marrow stromal cells. Exp Hematol. 2004; 32: 1238–1245.[CrossRef][Medline] [Order article via Infotrieve]
- Lijnen HR, Van Hoef B, Umans K, Collen D. Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor-1 (PAI-1). J Thromb Haemost. 2004; 2: 16–22.[CrossRef][Medline] [Order article via Infotrieve]
- Schäfer K, Konstantinides S. PAI-1 and vasculopathy: the debate continues. J Thromb Haemost. 2004; 2: 13–15.[Medline] [Order article via Infotrieve]
- Kawasaki T, Dewerchin M, Lijnen HR, Vermylen J, Hoylaerts MF. Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Blood. 2000; 96: 153–160.
[Abstract/Free Full Text] - Fay WP, Eitzman DT, Shapiro AD, Madison EL, Ginsburg D. Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood. 1994; 83: 351–356.
[Abstract/Free Full Text]
Related Article:
- Maintenance of Vascular Homeostasis by Bone Marrow–Derived Cells
- Julie Sainz and Masataka Sata
Arterioscler. Thromb. Vasc. Biol. 2006 26: 1196-1197.[Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  N. Yajima, M. Takahashi, H. Morimoto, Y. Shiba, Y. Takahashi, J. Masumoto, H. Ise, J. Sagara, J. Nakayama, S. Taniguchi, et al. Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice Circulation, June 17, 2008; 117(24): 3079 - 3087. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Satoh, T. Matoba, J. Suzuki, M. R. O'Dell, P. Nigro, Z. Cui, A. Mohan, S. Pan, L. Li, Z.-G. Jin, et al. Cyclophilin A Mediates Vascular Remodeling by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation Circulation, June 17, 2008; 117(24): 3088 - 3098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tanaka, M. Sata, T. Natori, J.-r. Kim-Kaneyama, K. Nose, M. Shibanuma, Y. Hirata, and R. Nagai Circulating progenitor cells contribute to neointimal formation in nonirradiated chimeric mice FASEB J, February 1, 2008; 22(2): 428 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Bentzon, C. S. Sondergaard, M. Kassem, and E. Falk Smooth Muscle Cells Healing Atherosclerotic Plaque Disruptions Are of Local, Not Blood, Origin in Apolipoprotein E Knockout Mice Circulation, October 30, 2007; 116(18): 2053 - 2061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. P. Fay, N. Garg, and M. Sunkar Vascular Functions of the Plasminogen Activation System Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1231 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Bentzon, C. Weile, C. S. Sondergaard, J. Hindkjaer, M. Kassem, and E. Falk Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2696 - 2702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sainz and M. Sata Maintenance of Vascular Homeostasis by Bone Marrow-Derived Cells. Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1196 - 1197. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||