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Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies

Nature Medicine volume 8, pages 1249–1256 (2002)Cite this article

In atherosclerosis, the vascular smooth muscle cell (VSMC) contributes to vessel wall inflammation and lipoprotein retention, as well as to the formation of the fibrous cap that provides stability to the plaque. The VSMC can undergo a proliferative response that underlies the development of in-stent restenosis, bypass graft occlusion and transplant vasculopathy. Although the benefit/risk of therapeutic inhibition of VSMC proliferation in atherosclerosis is unclear, experimental and human evidence strongly suggests the therapeutic potential of antiproliferative therapy for in-stent restenosis, bypass graft failure and other vascular proliferative disorders.

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Figure 1: Function of VSMCs during different stages of atherosclerosis.

D. Maizels

Figure 2: Simplified scheme of the cell cycle.

D. Maizels

Figure 3: VSMCs mediate proliferation, inflammation, matrix alterations and contraction.

D. Maizels

Figure 4: Mechanisms of action of rapamycin and E2F decoy.

D. Maizels

References

  1. Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Libby, P., Ridker, P.M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Ross, R. Cell biology of atherosclerosis. Annu. Rev. Physiol. 57, 791–804 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Ross, R. & Glomset, J.A. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180, 1332–1339 (1973).

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz, S.M., Virmani, R. & Rosenfeld, M.E. The good smooth muscle cells in atherosclerosis. Curr. Atheroscler. Rep. 2, 422–429 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Schwartz, S.M., deBlois, D. & O'Brien, E.R.M. The intima. Soil for atherosclerosis and restenosis. Circ. Res. 77, 445–465 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Fuster, V. Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: Insights from studies of vascular biology. Circulation 90, 2126–2146 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Velican, C. & Velican, D. Intimal thickening in developing coronary arteries and its relevance to atherosclerosis involvement. Atherosclerosis 23, 345–355 (1976).

    Article  Google Scholar 

  9. Schwartz, S.M. & Murry, C.E. Proliferation and the monoclonal origins of atherosclerotic lesions. Annu. Rev. Med. 49, 437–460 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Gordon, D., Reidy, M.A., Benditt, E.P. & Schwartz, S.M. Cell proliferation in human coronary arteries. Proc. Natl. Acad. Sci. USA 87, 4600–4604 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. O'Brien, E.R. et al. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. Circ. Res. 73, 223–231 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Katsuda, S., Boyd, H.C., Fligner, C., Ross, R. & Gown, A.M. Human atherosclerosis. III. Immunocytochemical analysis of the cell composition of lesions of young adults. Am. J. Pathol. 140, 907–914 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Scott, N.A. et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of procine coronary arteries. Circulation 93, 2178–2187 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. DeRuiter, M.C. et al. Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. Circ. Res. 80, 444–451 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Campbell, J.H., Han, C.L. & Campbell, G.R. Neointimal formation by circulating bone marrow cells. Ann. NY Acad. Sci. 947, 18–24 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Simper, D., Stalboerger, P.G., Panetta, C.J., Wang, S. & Caplice, N.M. Smooth muscle progenitor cells in human blood. Circulation 106, 1199–1204 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Braun-Dullaeus, R.C., Mann, M.J. & Dzau, V.J. Cell cycle progression. New therapeutic target for vascular proliferative disease. Circulation 98, 82–89 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Serruys, P.W. et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N. Engl. J. Med. 331, 489–495 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Mann, M.J. et al. Ex vivo gene therapy of human vascular bypass grafts with E2F decoy: The PREVENT single-centre, randomised, controlled trial. Lancet 354, 1493–1498 (1999).

    Article  CAS  PubMed  Google Scholar 

  23. Lindner, V. & Reidy, M.A. Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. Proc. Natl. Acad. Sci. USA 88, 3739–3743 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ferns, G.A. et al. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 253, 1129–1132 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Majeski, M.W., Lindner, V., Twardzik, D.R. & Reidy, M.A. Production of transforming growth factor β-1 during repair of arterial injury. J. Clin. Invest. 88, 904–910 (1991).

    Article  Google Scholar 

  26. Nabel, E.G. et al. Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo. J. Clin. Invest. 91, 1822–1829 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grant, M.B. et al. Localization of insulin-like growth factor I and inhibition of coronary smooth muscle cell growth by somatostatin analogues in human coronary smooth muscle cells. A potential treatment for restenosis? Circulation 89, 1511–1517 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Dzau, V.J., Gibbons, G.H. & Pratt, R.E. Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. Hypertension 18, II100–11105 (1991).

    CAS  PubMed  Google Scholar 

  29. Ignarro, L.J., Buga, G.M., Wood, K.S., Byrns, R.E. & Chaudhuri, G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl. Acad. Sci. USA 84, 9265–9269 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kinsella, M.G. & Wight, T.N. Modulation of sulfated proteoglycan synthesis by bovine aortic endothelial cells during migration. J. Cell. Biol. 102, 678–687 (1986).

    Article  Google Scholar 

  31. Elledge, S.J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664–1671 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Koepp, D.M., Harper, J.W. & Elledge, S.J. How the cyclin became a cyclin: Regulated proteolysis in the cell cycle. Cell 97, 431–434 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Sherr, C.J. Mammalian G1 cyclins and cell cycle progression. Proc. Assoc. Am. Phys. 107, 181–186 (1995).

    CAS  PubMed  Google Scholar 

  34. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Smith, R.C. et al. p21CIP1-mediated inhibition of cell proliferation by overexpression of the gax homeodomain gene. Genes Dev. 11, 1674–1689 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Narita, N., Heikinheimo, M., Bielinska, M., White, R.A. & Wilson, D.B. The gene for transcription factor GATA-6 resides on mouse chromosome 18 and is expressed in myocardium and vascular smooth muscle. Genomics 36, 345–348 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Perlman, H., Suzuki, E., Simonson, M., Smith, R.C. & Walsh, K. GATA-6 induces p21(Cip1) expression and G1 cell cycle arrest. J. Biol. Chem. 273, 13713–13718 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Guo, K., Andres, V. & Walsh, K. Nitric oxide-induced downregulation of Cdk2 activity and cyclin A gene transcription in vascular smooth muscle cells. Circulation 97, 2066–2072 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Ishida, A., Sasaguri, T., Kosaka, C., Nojima, H. & Ogata, J. Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells. J. Biol. Chem. 272, 10050–10057 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Jacks, T. & Weinberg, R.A. The expanding role of cell cycle regulators. Science 280, 1035–1036 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Hiromura, K., Pippin, J.W., Fero, M.L., Roberts, J.M. & Shankland, S.J. Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1). J. Clin. Invest. 103, 597–604 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Biro, S., Fu, Y.-M., Yu, Z.-X. & Epstein, S.E. Inhibitory effects of antisense oligodeoxynucleotides targeting c-myc mRNA on smooth muscle cell proliferation and migration. Proc. Natl. Acad. Sci. USA 90, 654–658 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fukui, R. et al. Inhibition of smooth muscle cell migration by the p21 cyclin-dependent kinase inhibitor (Cip1). Atherosclerosis 132, 53–59 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Shi, Y. et al. Transcatheter delivery of c-myc antisense oligomers reduces neointimal formation in a porcine model of coronary artery balloon injury. Circulation 90, 944–951 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Braun-Dullaeus, R.C., Mann, M.J., Ziegler, A., von der Leyen, H.E. & Dzau, V.J. A novel role for the cyclin-dependent kinase inhibitor p27KIP1 in angiotensin II-stimulated vascular smooth muscle cell hypertrophy. J. Clin. Invest. 104, 815–823 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mann, M.J. et al. Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts. J. Clin. Invest. 99, 1295–1301 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Perkins, N.D. et al. Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator. Science 275, 523–527 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Gilroy, D.W., Saunders, M.A., Sansores-Garcia, L., Matijevic-Aleksic, N. & Wu, K.K. Cell cycle-dependent expression of cyclooxygenase-2 in human fibroblasts. Faseb J. 15, 288–290 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Kleemann, R. et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. von der Leyen, H.E. et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc. Natl. Acad. Sci. USA 92, 1137–1141 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qian, H., Neplioueva, V., Shetty, G.A., Channon, K.M. & George, S.E. Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits. Circulation 99, 2979–2982 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Gershlick, A.H. Treating atherosclerosis: Local drug delivery from laboratory studies to clinical trials. Atherosclerosis 160, 259–271 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Sehgal, S.N., Baker, H. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. (Tokyo) 28, 727–732 (1975).

    Article  CAS  Google Scholar 

  54. Gregory, C.R., Huie, P., Billingham, M.E. & Morris, R.E. Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury. Its effect on cellular, growth factor, and cytokine response in injured vessels. Transplantation 55, 1409–1418 (1993).

    Article  CAS  PubMed  Google Scholar 

  55. Braun-Dullaeus, R.C. et al. Cell cycle protein expression in vascular smooth muscle cells in vitro and in vivo is regulated through phosphatidylinositol 3-kinase and mammalian target of rapamycin. Arterioscler. Thromb. Vasc. Biol. 21, 1152–1158 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Gallo, R. et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 99, 2164–2170 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Zheng, X.F., Florentino, D., Chen, J., Crabtree, G.R. & Schreiber, S.L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121–130 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Kuo, C.J. et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358, 70–73 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. Graves, L.M. et al. cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc. Natl. Acad. Sci. USA 92, 7222–7226 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Poon, M. et al. Rapamycin inhibits vascular smooth muscle cell migration. J. Clin. Invest. 98, 2277–2283 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Giasson, E. & Meloche, S. Role of p70 S6 protein kinase in angiotensin II-induced protein synthesis in vascular smooth muscle cells. J. Biol. Chem. 270, 5225–5231 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Morice, M.C. et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N. Engl. J. Med. 346, 1773–1780 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Jordan, M.A., Toso, R.J., Thrower, D. & Wilson, L. Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. Proc. Natl. Acad. Sci. USA 90, 9552–9556 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Axel, D.I. et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 96, 636–645 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Liistro, F. et al. First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: Immediate and long- term clinical and angiographic outcome. Circulation 105, 1883–1886 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Gray, N., Detivaud, L., Doerig, C. & Meijer, L. ATP-site directed inhibitors of cyclin-dependent kinases. Curr. Med. Chem. 6, 859–875 (1999).

    CAS  PubMed  Google Scholar 

  67. Ruef, J. et al. Flavopiridol inhibits smooth muscle cell proliferation in vitro and neointimal formation in vivo after carotid injury in the rat. Circulation 100, 659–665 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Brooks, E.E. et al. CVT-313, a specific and potent inhibitor of CDK2 that prevents neointimal proliferation. J. Biol. Chem. 272, 29207–29211 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Grise, M.A. et al. Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 105, 2737–2740 (2002).

    Article  PubMed  Google Scholar 

  70. Waksman, R. et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 101, 2165–2171 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Scott, S., O'Sullivan, M., Hafizi, S., Shapiro, L.M. & Bennett, M.R. Human vascular smooth muscle cells from restenosis or in-stent stenosis sites demonstrate enhanced responses to p53: Implications for brachytherapy and drug treatment for restenosis. Circ. Res. 90, 398–404 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Morishita, R. et al. Single intraluminal delivery of antisense cdc2 kinase and proliferating-cell nuclear antigen oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc. Natl. Acad. Sci. USA 90, 8474–8478 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Simons, M., Edelman, E.R. & Rosenberg, R.D. Antisense proliferating cell nuclear antigen oligonucleotides inhibit intimal hyperplasia in a rat carotid artery injury model. J. Clin. Invest. 93, 2351–2356 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kutryk, M.J. et al. Local intracoronary administration of antisense oligonucleotide against c-myc for the prevention of in-stent restenosis: results of the randomized investigation by the Thoraxcenter of antisense DNA using local delivery and IVUS after coronary stenting (ITALICS) trial. J. Am. Coll. Cardiol. 39, 281–287 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Frimerman, A. et al. Chimeric DNA-RNA hammerhead ribozyme to proliferating cell nuclear antigen reduces stent-induced stenosis in a porcine coronary model. Circulation 99, 697–703 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Yang, Z.-Y. et al. Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. Proc. Natl. Acad. Sci. USA 93, 7905–7910 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yonemitsu, Y., Kaneda, Y., Hataa, Y., Nakashima, Y. & Sueishi, K. Wild-type p53 gene transfer: a novel therapeutic strategy for neointimal hyperplasia after arterial injury. Ann. NY Acad. Sci. 811, 395–399 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, D. et al. Downregulation of cyclin-dependent kinase 2 activity and cyclin A promoter activity in vascular smooth muscle cells by p27KIP1, an inhibitor of neointima formation in the rat carotid artery. J. Clin. Invest. 99, 2334–2341 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Mano, T., Luo, Z., Malendowicz, S.L., Evans, T. & Walsh, K. Reversal of GATA-6 downregulation promotes smooth muscle differentiation and inhibits intimal hyperplasia in balloon-injured rat carotid artery. Circ. Res. 84, 647–654 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Chang, M.W. et al. Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product. Science 267, 518–522 (1995).

    Article  CAS  PubMed  Google Scholar 

  81. von der Leyen, H.E. & Dzau, V.J. Therapeutic potential of nitric oxide synthase gene manipulation. Circulation 103, 2760–2765 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Morishita, R. et al. A gene therapy strategy using a transcription factor decoy of the E2F binding site inhibits smooth muscle proliferation in vivo. Proc. Natl. Acad. Sci. USA 92, 5855–5859 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mangi, A.A. & Dzau, V.J. Gene therapy for human bypass grafts. Ann. Med. 33, 153–155. (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S.M. Schwartz for suggestions and criticisms in the preparation of this manuscript. V.J.D. is the recipient of a National Heart Lung and Blood Institute MERIT Award. R.C.B.-D. is supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 547:A7, Graduiertenkolleg 534). D.G.S. is a scholar of the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 534).

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  1. Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA

    Victor J. Dzau

  2. Department of Medicine, Giessen University, Giessen, Germany

    Ruediger C. Braun-Dullaeus & Daniel G. Sedding

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Dzau, V., Braun-Dullaeus, R. & Sedding, D. Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nat Med 8, 1249–1256 (2002). https://doi.org/10.1038/nm1102-1249

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