doi: 10.1161/01.ATV.0000220378.06854.35
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Editorials |
Maintenance of Vascular Homeostasis by Bone Marrow–Derived Cells
From the Departments of Cardiovascular Medicine (J.S., M.S.) and Advanced Clinical Science and Therapeutics (M.S.), University of Tokyo, Graduate School of Medicine, Japan.
Correspondence to Dr Masataka Sata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.net
The accumulation of smooth muscle cells (SMCs) plays a principal role in the pathogenesis of various vascular diseases. It has been hypothesized that dedifferentiated SMCs migrate from the media to the subendothelial space, where they proliferate and contribute to atherogenesis.1 Similarly, it has been assumed that all of the neointimal cells in postangioplasty restenosis and graft vasculopathy are derived from adjacent medial cells. In addition to this traditional concept, recent evidence suggests that bone marrow-derived circulating precursors can also give rise to endothelial-like cells and/or smooth muscle-like cells that contribute to vascular repair, remodeling, and lesion formation in animals2–4 and in humans.5 However, the contribution of bone marrow-derived cells to vascular remodeling still remains controversial.6 It remained to be clarified how highly "bone marrow-derived circulating progenitor cells" can differentiate into mature SMCs phenotypically and functionally.7
See page 1254
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Schäfer et al provide convincing evidence that bone marrow-derived cells significantly participate in neointimal formation induced by carotid arterial injury with ferric chloride (FeCl3).8 Using two types of bone marrow chimeric mice, the authors found that 
21% of neointimal cells and 38% of medial cells originated from the bone marrow in this mouse model of vascular injury. A significant amount of bone marrow-derived cells in the media and neointima expressed 
-smooth muscle actin and, to less extent, smooth muscle myosin heavy chain. Interestingly, the bone marrow-derived cells did not participate in reendothelialization as determined by double-immunostaining for von Willebrand factor (vWF) and LacZ.
Numerous reports have demonstrated that neointimal cells are heterogeneous and that SMCs in vascular lesions are composed of cells of diverse origin.3,9,10 We reported that the cellular constituents of a lesion differ depending on the type of vascular injury3 and that distinct mechanisms may regulate neointimal formation in different models. In our mouse model of endovascular injury which results in robust contribution of bone marrow–derived cells to neointimal hyperplasia,11 insertion of a large wire dilates femoral artery with complete endothelial denudation and massive medial cell apoptosis. Severe injury with subsequent high expression of cytokines and chemokines appears to be required for bone marrow–derived progenitors to participate in lesion formation.3
Schäfer et al applied FeCl3 to adventitial side of carotid artery.8 FeCl3 enhances formation of highly reactive oxygen species, which in turn damage cells and cause lipid peroxidation. FeCl3 induced severe vascular injury characterized by endothelial denudation, medial smooth muscle cell necrosis, and occlusive thrombus formation. In this model, bone marrow–derived cells could be detected inside the arterial wall only at the time points later than one week after injury, although bone marrow–derived cells could be abundantly detected in the vascular lumen of the injured artery at earlier time points. At three weeks, the injured artery was fully reendothelialized with intimal and medial hyperplasia that was essentially composed of SMCs,12 like the lesions induced by other types of mechanical injuries.11,13–15 These findings are comparable with a previous report on the temporal and spatial characterization of cellular constituents during neointimal hyperplasia after wire-mediated vascular injury,16 in which CD45-positive hematopoietic cells accumulated on the luminal side of the artery at one week and were gradually replaced by -smooth muscle actin positive cells. It is likely that FeCl3 caused severe vascular injury with massive cell death and thrombus formation, which resulted in robust recruitment of circulating bone marrow–derived for the repair of the damaged artery containing only few residual cells.
Taking advantage of FeCl3-induced vascular injury model that is characterized by thrombus formation and fibrin deposition at earlier time points, Schäfer et al investigated the role of plasminogen activator inhibitor (PAI-1) in the pathogenesis of neointimal formation. PAI-1 has been proposed to be involved in the pathogenesis of atherosclerosis.17 PAI-1 expression is upregulated inside the arterial wall in animal models of atherosclerosis18 and neointima formation after vascular injury.19 Schäfer et al found that FeCl3-induced vascular injury resulted in greater neointimal formation and lumen stenosis in PAI-1–/– recipient mice which had undergone bone marrow transplantation (BMT) from PAI-1–/– donor mice (BMTPAI-1–/–
PAI-1–/–) than those in wild-type (WT) recipient mice which had undergone BMT from WT donor (BMTWTWT). BMT from PAI-1–/– mice to WT mice (BMTPAI-1–/–WT) resulted in a decrease in PAI-1 amount inside the arterial wall from 20% to 7%, thereby indicating that bone marrow–derived cells contribute to local expression of PAI-1. Deficiency of PAI-1 selectively in bone marrow affected neither neointimal area nor luminal stenosis. Notably, expression of PAI-1 by small number of bone marrow–derived neointimal cells was sufficient to suppress neointima formation in BMTWTPAI-1–/– mice. It was suggested that PAI-1 expressed either by bone marrow–derived cells or by local vascular cells appeared to be sufficient to suppress neointimal growth after vascular injury, presumably in a paracrine manner (Figure). The precise molecular mechanism by which local expression of PAI-1 effectively reduced neointimal formation should be defined in detail. In this regard, PAI-1 was reported to modulate extracellular matrix degradation that regulates adhesion and migration of SMCs.20
|
Finally, the findings by Schäfer et al suggest that bone marrow–derived progenitors play a role in vascular healing and remodeling not only by differentiating into endothelial-like cells or smooth muscle–like cells but also by secreting humoral factors that potentially regulate cell migration and/or proliferation of neighboring vascular cells. Previous reports have showed that replacement of bone marrow cells with those from genetically-modified animals significantly influenced the vascular lesions induced by hyperlipidemia and mechanical arterial injury.21–25 Bone marrow–derived circulating progenitors might be an additional source of essential cellular and humoral components to maintain vascular homeostasis, particularly when artery is severely injured. Further investigation on the roles of circulating progenitor cells in vascular physiology and pathophysiology is warranted.
 |
Acknowledgments |
|---|
This study was supported in part by grants from Ministry of Education, Culture, Sports, Science, and Technology, Ministry of Health, Labor, and Welfare, and Japan Society for the Promotion of Science.
|
References |
|---|
 Top References |
|---|
1. Ross R. Rous-Whipple Award Lecture. Atherosclerosis:. a defense mechanism gone awry. Am J Pathol. 1993; 143: 987–1002.[Medline] [Order article via Infotrieve]
2. 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]
3. 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.
4. 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]
5. 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.
6. Sata M, Tanaka K, Nagai R. Origin of smooth muscle progenitor cells: different conclusions from different models. Circulation. 2003; 107: e106–e107.
7. Sata M. The role of circulating vascular progenitors in angiogenesis, vascular healing, and pulmonary hypertension: lessons from animal models. Arterioscler Thromb Vasc Biol. 2006; 26: 1008–1014.
8. Schafer K, Schroeter MR, Dellas C, Puls M, Nitsche M, Weiss E, Hasenfuss G, Konstantinides SV. Plasminogen activator inhibitor-1 from bone marrow–derived cells suppresses neointimal formation after vascular injury in mice. Arterioscler Thromb Vasc Biol. 2006; 26: 1254–1259.[CrossRef][Medline] [Order article via Infotrieve]
9. Li S, Fan YS, Chow LH, Van Den Diepstraten C, van Der Veer E, Sims SM, Pickering JG. Innate diversity of adult human arterial smooth muscle cells: cloning of distinct subtypes from the internal thoracic artery. Circ Res. 2001; 89: 517–525.
10. Zalewski A, Shi Y, Johnson AG. Diverse origin of intimal cells: smooth muscle cells, myofibroblasts, fibroblasts, and beyond? Circ Res. 2002; 91: 652–655.
11. Sata M, Maejima Y, Adachi F, Fukino K, Saiura A, Sugiura S, Aoyagi T, Imai Y, Kurihara H, Kimura K, Omata M, Makuuchi M, Hirata Y, Nagai R. A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol. 2000; 32: 2097–2104.[CrossRef][Medline] [Order article via Infotrieve]
12. Konstantinides S, Schafer 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.
13. Carmeliet P, Moons L, Stassen J-M, Mol MD, Bouche A, van den Oord JJ, Kockx M, Collen D. Vascular wound healing and neointima formation induced by perivascular electric injury in mice. Am J Pathol. 1997; 150: 761–776.[Abstract]
14. Moroi M, Zhang L, Yasuda T, Virmani R, Gold HK, Fishman MC, Huang PL. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest. 1998; 101: 1225–1232.[Medline] [Order article via Infotrieve]
15. Kumar A, Lindner V. Remodeling with neointima formation in the mouse carotid artery after cessation of blood flow. Arterioscler Thromb Vasc Biol. 1997; 17: 2238–2244.
16. Shoji M, Sata M, Fukuda D, Tanaka K, Sato T, Iso Y, Shibata M, Suzuki H, Koba S, Geshi E, Katagiri T. Temporal and spatial characterization of cellular constituents during neointimal hyperplasia after vascular injury: Potential contribution of bone-marrow-derived progenitors to arterial remodeling. Cardiovasc Pathol. 2004; 13: 306–312.[CrossRef][Medline] [Order article via Infotrieve]
17. Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blomback M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987; 2: 3–9.[CrossRef][Medline] [Order article via Infotrieve]
18. Schafer K, Muller 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.
19. Hasenstab D, Forough R, Clowes AW. Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2 increase after arterial injury in rats. Circ Res. 1997; 80: 490–496.
20. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature. 1996; 383: 441–443.[CrossRef][Medline] [Order article via Infotrieve]
21. Linton MF, Atkinson JB, Fazio S. Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science. 1995; 267: 1034–1037.
22. Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest. 2005; 115: 3149–3156.[CrossRef][Medline] [Order article via Infotrieve]
23. Huo Y, Zhao L, Hyman MC, Shashkin P, Harry BL, Burcin T, Forlow SB, Stark MA, Smith DF, Clarke S, Srinivasan S, Hedrick CC, Pratico D, Witztum JL, Nadler JL, Funk CD, Ley K. Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004; 110: 2024–2031.
24. Boehm M, Olive M, True AL, Crook MF, San H, Qu X, Nabel EG. Bone marrow-derived immune cells regulate vascular disease through a p27(Kip1)-dependent mechanism. J Clin Invest. 2004; 114: 419–426.[CrossRef][Medline] [Order article via Infotrieve]
25. Manka D, Forlow SB, Sanders JM, Hurwitz D, Bennett DK, Green SA, Ley K, Sarembock IJ. Critical role of platelet P-selectin in the response to arterial injury in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol. 2004; 24: 1124–1129.
Related Article:
Arterioscler Thromb Vasc Biol 2006 26: 1254-1259.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||