The impact of progenitor cells in atherosclerosis

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Abstract

During the pathogenesis of arteriosclerosis, endothelial cells on the arterial wall damaged by various means were initially thought to be replaced by replication of neighboring cells. Smooth-muscle cells (SMCs) were also thought to migrate from the media into the intima, where they constituted arteriosclerotic lesions. This concept has been challenged, however, by the discovery that progenitor cells in the circulation and adventitia contribute to endothelial repair and SMC accumulation. Studies have demonstrated that atherosclerosis is a pathophysiologic process initiated by endothelial death in specific areas, such as bifurcation regions, and with subsequent replacement by endothelial progenitor cells. Differentiation of the neoendothelial cells into mature endothelium takes several days or weeks, during which LDL deposits in the intima. Blood mononuclear cells also adhere to neoendothelial cells and migrate into the subendothelial space. Meanwhile, progenitor cells from blood and the adventitia migrate into the intima, where they proliferate and differentiate into neo-SMCs. All risk factors for atherosclerosis can exert their effects on the vessel wall partly via increase in endothelial turnover, inhibition of progenitor-cell differentiation, and promotion of smooth-muscle and macrophage accumulation in lesions. Thus, progenitor cells comprise the main cell source responsible for the formation of atherosclerotic lesions, which appear in the context of inflammatory disease. Here I provide an update on research and discuss the role of progenitor cells in the pathogenesis of atherosclerosis.

Key Points

  • Endothelial damage, dysfunction or both are critical events in the initiation of atherosclerotic-plaque development, and regeneration is of particular importance

  • Progenitor cells are a likely source of endothelial repair and smooth-muscle accumulation in atherosclerotic lesions

  • Bone-marrow-derived endothelial progenitor cells are mobilized to re-establish an intact endothelial layer following denudation of endothelium

  • The homing mechanisms responsible for recruitment of endothelial progenitor cells to the damaged vessel surface or for angiogenesis within the vessel wall need to be investigated

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Figure 1: En face photographs showing endothelial cells of mouse aortas.
Figure 2: Schematic representation of the initiation of atherosclerosis.
Figure 3: En face staining of aortic endothelial cells with a substrate X-galactosidase to show the recipient origin after grafting.
Figure 4: Schematic representation of progression of atherosclerosis.

References

  1. 1

    Ross R et al. (1977) Response to injury and atherogenesis. Am J Pathol 86: 675–684

  2. 2

    Asahara T et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967

  3. 3

    Rafii S (2000) Circulating endothelial precursors: mystery, reality, and promise. J Clin Invest 105: 17–19

  4. 4

    Werner N et al. (2002) Bone marrow-derived progenitor cells modulate vascular reendothelialization and neointimal formation: effect of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition. Arterioscler Thromb Vasc Biol 22: 1567–1572

  5. 5

    Xu Q et al. (2003) Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in apoE-deficient mice. Circ Res 93: e76–e86

  6. 6

    Simper D et al. (2003) Endothelial progenitor cells are decreased in blood of cardiac allograft patients with vasculopathy and endothelial cells of noncardiac origin are enriched in transplant atherosclerosis. Circulation 108: 143–149

  7. 7

    Shimizu K et al. (2001) Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med 7: 738–741

  8. 8

    Saiura A et al. (2001) Circulating smooth muscle progenitor cells contribute to atherosclerosis. Nat Med 7: 382–383

  9. 9

    Han CI et al. (2001) Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res 38: 113–119

  10. 10

    Hillebrands JL et al. (2001) Origin of neointimal endothelium and α-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest 107: 1411–1422

  11. 11

    Li J et al. (2001) Vascular smooth muscle cells of recipient origin mediate intimal expansion after aortic allotransplantation in mice. Am J Pathol 158: 1943–1947

  12. 12

    Sata M et al. (2002) Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 8: 403–409

  13. 13

    Hu Y et al. (2002) Smooth muscle cells in transplant atherosclerotic lesions are originated from recipients, but not bone marrow progenitor cells. Circulation 106: 1834–1839

  14. 14

    Urbich C and Dimmeler S (2004) Endothelial progenitor cells functional characterization. Trends Cardiovasc Med 14: 318–322

  15. 15

    Schwartz SM and Benditt EP (1973) Cell replication in the aortic endothelium: a new method for study of the problem. Lab Invest 28: 699–707

  16. 16

    Schwartz SM and Benditt EP (1976) Clustering of replicating cells in aortic endothelium. Proc Natl Acad Sci USA 73: 651–653

  17. 17

    Schwartz SM and Benditt EP (1977) Aortic endothelial cell replication, I. Effects of age and hypertension in the rat. Circ Res 41: 248–255

  18. 18

    Davies PF et al. (1986) Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro. Proc Natl Acad Sci USA 83: 2114–2117

  19. 19

    Werner N et al. (2003) Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res 93: e17–e24

  20. 20

    Walter DH et al. (2002) Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 105: 3017–3024

  21. 21

    Strehlow K et al. (2003) Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 107: 3059–3065

  22. 22

    Laufs U et al. (2004) Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 109: 220–226

  23. 23

    Kong D et al. (2004) Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation 110: 2039–2046

  24. 24

    Aicher A et al. (2003) Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9: 1370–1376

  25. 25

    Griese DP et al. (2003) Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation 108: 2710–2715

  26. 26

    Kong D et al. (2004) Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 109: 1769–1775

  27. 27

    Ziegelhoeffer T et al. (2004) Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res 94: 230–238

  28. 28

    Lambiase PD et al. (2004) Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support. Circulation 109: 2986–2992

  29. 29

    Hristov M et al. (2003) Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol 23: 1185–1189

  30. 30

    Zou Y et al. (1998) Mouse model of venous bypass graft arteriosclerosis. Am J Pathol 153: 1301–1310

  31. 31

    Dietrich H et al. (2000) Rapid development of vein graft atheroma in ApoE-deficient mice. Am J Pathol 157: 659–669

  32. 32

    Mayr M et al. (2000) Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases. FASEB J 14: 261–270

  33. 33

    Hu Y et al. (2003) Endothelial replacement and angiogenesis in arteriosclerotic lesions of allografts are contributed by circulating progenitor cells. Circulation 108: 3122–3127

  34. 34

    Quaini F et al. (2002) Chimerism of the transplanted heart. N Engl J Med 346: 5–15

  35. 35

    Vasa M et al. (2001) Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 103: 2885–2890

  36. 36

    Vasa M et al. (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89: E1–E7

  37. 37

    Dimmeler S et al. (2001) HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 108: 391–397

  38. 38

    Hill JM et al. (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348: 593–600

  39. 39

    Op den Buijs J et al. (2004) Mathematical modeling of vascular endothelial layer maintenance: the role of endothelial cell division, progenitor cell homing, and telomere shortening. Am J Physiol Heart Circ Physiol 287: H2651–H2688

  40. 40

    Kahlon R et al. (1992) Angiogenesis in atherosclerosis. Can J Cardiol 8: 60–64

  41. 41

    Moulton KS et al. (1999) Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99: 1726–1732

  42. 42

    Ross JS et al. (2001) Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann NY Acad Sci 947: 271–292

  43. 43

    Rotmans JI et al. (2005) In vivo cell seeding with anti-CD34 antibodies successfully accelerates endothelialization but stimulates intimal hyperplasia in porcine arteriovenous expanded polytetrafluoroethylene grafts. Circulation 112: 12–18

  44. 44

    Simper D et al. (2002) Smooth muscle progenitor cells in human blood. Circulation 106: 1199–1204

  45. 45

    Fukuda D et al. (2005) Potent inhibitory effect of sirolimus on circulating vascular progenitor cells. Circulation 111: 926–931

  46. 46

    Hu Y et al. (2004) Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113: 1258–1265

  47. 47

    Tintut Y et al. (2003) Multilineage potential of cells from the artery wall. Circulation 108: 2505–2510

  48. 48

    Zeiffer U et al. (2004) Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines. Circ Res 94: 776–784

  49. 49

    Xu Y et al. (2004) Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice. Arterioscler Thromb Vasc Biol 24: 477–482

  50. 50

    Hu Y et al. (2002) Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res 91: e13–e20

  51. 51

    Caplice NM et al. (2003) Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci USA 100: 4754–4759

  52. 52

    Tanaka K et al. (2003) Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res 93: 783–790

  53. 53

    Owens GK (1989) Growth response of tetraploid smooth muscle cells to balloon embolectomy-induced vascular injury in the spontaneously hypertensive rat. Am Rev Respir Dis 140: 1467–1470

  54. 54

    Yeh ET et al. (2003) Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 108: 2070–2073

  55. 55

    Wagers AJ et al. (2002) Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297: 2256–2259

  56. 56

    Torsney E et al. (2005) Adventitial progenitor cells contribute to arteriosclerosis. Trends Cardiovasc Med 15: 64–68

  57. 57

    Libby P and Aikawa M (1998) New insights into plaque stabilisation by lipid lowering. Drugs 56 (Suppl 1): S9–S13

  58. 58

    Bompais H et al. (2004) Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood 103: 2577–2584

  59. 59

    Schwartz SM and Benditt EP (1972) Studies on aortic intima. I. Structure and permeability of rat thoracic aortic intima. Am J Pathol 66: 241–264

  60. 60

    Rossig L et al. (2004) Endothelial progenitor cells at work: not mature yet, but already stress-resistant. Arterioscler Thromb Vasc Biol 24: 1977–1979

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Acknowledgements

I acknowledge all collaborators who contributed to the work summarized in the review. I thank Dr E Torsney for critical reading of the manuscript. This work was supported by grants from the British Heart Foundation, Oak Foundation and the European Community's Sixth Framework Programme for Research.

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Correspondence to Qingbo Xu.

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The author declares no competing financial interests.

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Xu, Q. The impact of progenitor cells in atherosclerosis. Nat Rev Cardiol 3, 94–101 (2006) doi:10.1038/ncpcardio0396

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