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  • Review Article
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The importance of the endothelium in atherothrombosis and coronary stenting

Nature Reviews Cardiology volume 9, pages 439–453 (2012)Cite this article

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A Correction to this article was published on 23 May 2013

This article has been updated

Abstract

Deployment of drug-eluting stents instead of bare-metal stents has dramatically reduced restenosis rates, but rates of very late stent thrombosis (>1 year postimplantation) have increased. Vascular endothelial cells normally provide an efficient barrier against thrombosis, lipid uptake, and inflammation. However, endothelium that has regenerated after percutaneous coronary intervention is incompetent in terms of its integrity and function, with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production. Delayed arterial healing, characterized by poor endothelialization, is the primary cause of late (1 month–1 year postimplantation) and very late stent thrombosis following implantation of drug-eluting stents. Impairment of vasorelaxation in nonstented proximal and distal segments of stented coronary arteries is more severe with drug-eluting stents than bare-metal stents, and stent-induced flow disturbances resulting in complex spatiotemporal shear stress can also contribute to increased thrombogenicity and inflammation. The incompetent endothelium leads to late stent thrombosis and the development of in-stent neoatherosclerosis. The process of neoatherosclerosis occurs more rapidly, and more frequently, following deployment of drug-eluting stents than bare-metal stents. Improved understanding of vascular biology is crucial for all cardiologists, and particularly interventional cardiologists, as maintenance of a competently functioning endothelium is critical for long-term vascular health.

Key Points

  • Normal vascular endothelium produces many molecules with antithrombotic properties, including nitric oxide, prostacyclin, tissue plasminogen activator, thrombomodulin, heparin-like molecules, and tissue factor pathway inhibitor

  • The integrity of the endothelial barrier is conferred by intercellular junction complexes that regulate signal transduction and endothelial permeability

  • Stent implantation causes intravascular injury and endothelial denudation; the regenerated endothelium is incompetent with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production

  • Stent implantation causes local blood flow disturbances associated with complex spatiotemporal changes in shear stress, which can change the endothelium phenotype from quiescent to inflammatory and increase its thrombogenicity

  • The regenerated incompetent endothelium lacks antithrombotic and antiatherogenic properties; this deficiency can lead to late and very late stent thrombosis, as well as the development of in-stent neoatherosclerosis

  • Use of drug-eluting stents is associated with accelerated progression and an increased prevalence of in-stent neoatherosclerosis versus bare-metal stents

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Figure 1: The structure and function of healthy endothelium.
Figure 2: Postulated G-protein-mediated signal transduction process in normal and regenerating endothelial cells.
Figure 3: Radiographs and electron micrographs from a 71-year-old woman who died of stroke.
Figure 4: Transmission electron micrographs of endothelial cell junctions in rabbit iliac arteries 14 days after stent implantation.
Figure 5: Dual immunofluorescence-labelled images showing PECAM-1 (green) and thrombomodulin (red) expression in stented and nonstented segments of rabbit iliac arteries.
Figure 6: Stent-induced flow disturbances affect thrombogenicity and re-endothelialization following stent implantation.
Figure 7: In vitro evaluation of blood flow and endothelialization after stenting.
Figure 8: Neoatherosclerosis following the deployment of bare-metal and drug-eluting stents in human coronary arteries.

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Change history

  • 03 April 2013

    In the version of this article originally published online and in print, the following sentence should have been included in the Figure 3 legend: Parts c, e, and h were previously published in Guagliumi, G. et al. Images in cardiovascular medicine. Sirolimus-eluting stent implanted in human coronary artery for 16 months: pathological findings. Circulation 107, 1340–1341 (2003). The error has been corrected in the HTML and PDF versions of the article.

References

  1. Serruys, P. W., Kutryk, M. J. & Ong, A. T. Coronary-artery stents. N. Engl. J. Med. 354, 483–495 (2006).

    CAS  PubMed  Google Scholar 

  2. 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).

    CAS  PubMed  Google Scholar 

  3. Ryan, J., Linde-Zwirble, W., Engelhart, L., Cooper, L. & Cohen, D. J. Temporal changes in coronary revascularization procedures, outcomes, and costs in the bare-metal stent and drug-eluting stent eras: results from the US Medicare program. Circulation 119, 952–961 (2009).

    PubMed  Google Scholar 

  4. Stone, G. W. et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N. Engl. J. Med. 350, 221–231 (2004).

    CAS  PubMed  Google Scholar 

  5. Lagerqvist, B. et al. Stent thrombosis in Sweden: a report from the Swedish Coronary Angiography and Angioplasty Registry. Circ. Cardiovasc. Interv. 2, 401–408 (2009).

    PubMed  Google Scholar 

  6. Joner, M. et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J. Am. Coll. Cardiol. 48, 193–202 (2006).

    PubMed  Google Scholar 

  7. Finn, A. V. et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 115, 2435–2441 (2007).

    PubMed  Google Scholar 

  8. Leon, M. B. et al. Improved late clinical safety with zotarolimus-eluting stents compared with paclitaxel-eluting stents in patients with de novo coronary lesions: 3-year follow-up from the ENDEAVOR IV (randomized comparison of zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease) trial. JACC Cardiovasc. Interv. 3, 1043–1050 (2010).

    PubMed  Google Scholar 

  9. Baber, U. et al. Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials. J. Am. Coll. Cardiol. 58, 1569–1577 (2011).

    CAS  PubMed  Google Scholar 

  10. de la Torre Hernandez, J. M. et al. Thrombosis of second-generation drug-eluting stents in real practice results from the multicenter Spanish registry ESTROFA-2 (Estudio Español Sobre Trombosis de Stents Farmacoactivos de Segunda Generacion-2). JACC Cardiovasc. Interv. 3, 911–919 (2010).

    PubMed  Google Scholar 

  11. Stefanini, G. G. et al. Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial. Lancet 378, 1940–1948 (2011).

    CAS  PubMed  Google Scholar 

  12. Mehta, D. & Malik, A. B. Signaling mechanisms regulating endothelial permeability. Physiol. Rev. 86, 279–367 (2006).

    CAS  PubMed  Google Scholar 

  13. Frank, P. G., Pavlides, S. & Lisanti, M. P. Caveolae and transcytosis in endothelial cells: role in atherosclerosis. Cell Tissue Res. 335, 41–47 (2009).

    CAS  PubMed  Google Scholar 

  14. Simionescu, M. & Antohe, F. Functional ultrastructure of the vascular endothelium: changes in various pathologies. Handb. Exp. Pharmacol. 176, 41–69 (2006).

    Google Scholar 

  15. Jimenez, J. M. & Davies, P. F. Hemodynamically driven stent strut design. Ann. Biomed. Eng. 37, 1483–1494 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. Xu, J. & Zou, M. H. Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation 120, 1266–1286 (2009).

    PubMed  PubMed Central  Google Scholar 

  17. Wu, K. K. & Thiagarajan, P. Role of endothelium in thrombosis and hemostasis. Annu. Rev. Med. 47, 315–331 (1996).

    CAS  PubMed  Google Scholar 

  18. Kwaan, H. C. & Samama, M. M. The significance of endothelial heterogeneity in thrombosis and hemostasis. Semin. Thromb. Hemost. 36, 286–300 (2010).

    PubMed  Google Scholar 

  19. Rogers, C., Tseng, D. Y., Squire, J. C. & Edelman, E. R. Balloon-artery interactions during stent placement: a finite element analysis approach to pressure, compliance, and stent design as contributors to vascular injury. Circ. Res. 84, 378–383 (1999).

    CAS  PubMed  Google Scholar 

  20. Dejana, E., Orsenigo, F., Molendini, C., Baluk, P. & McDonald, D. M. Organization and signaling of endothelial cell-to-cell junctions in various regions of the blood and lymphatic vascular trees. Cell Tissue Res. 335, 17–25 (2009).

    PubMed  Google Scholar 

  21. Dejana, E., Tournier-Lasserve, E. & Weinstein, B. M. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev. Cell 16, 209–221 (2009).

    CAS  PubMed  Google Scholar 

  22. Furuse, M. et al. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123, 1777–1788 (1993).

    CAS  PubMed  Google Scholar 

  23. Nitta, T. et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J. Cell Biol. 161, 653–660 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Imhof, B. A. & Aurrand-Lions, M. Adhesion mechanisms regulating the migration of monocytes. Nat. Rev. Immunol. 4, 432–444 (2004).

    CAS  PubMed  Google Scholar 

  25. Vestweber, D. Lymphocyte trafficking through blood and lymphatic vessels: more than just selectins, chemokines and integrins. Eur. J. Immunol. 33, 1361–1364 (2003).

    PubMed  Google Scholar 

  26. Lampugnani, M. G. & Dejana, E. Interendothelial junctions: structure, signalling and functional roles. Curr. Opin. Cell Biol. 9, 674–682 (1997).

    CAS  PubMed  Google Scholar 

  27. Goodenough, D. A. & Paul, D. L. Beyond the gap: functions of unpaired connexon channels. Nat. Rev. Mol. Cell Biol. 4, 285–294 (2003).

    CAS  PubMed  Google Scholar 

  28. Muller, W. A., Weigl, S. A., Deng, X. & Phillips, D. M. PECAM–1 is required for transendothelial migration of leukocytes. J. Exp. Med. 178, 449–460 (1993).

    CAS  PubMed  Google Scholar 

  29. Newman, P. J. et al. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247, 1219–1222 (1990).

    CAS  PubMed  Google Scholar 

  30. Sanderson, M. J., Charles, A. C., Boitano, S. & Dirksen, E. R. Mechanisms and function of intercellular calcium signaling. Mol. Cell Endocrinol. 98, 173–187 (1994).

    CAS  PubMed  Google Scholar 

  31. Bazzoni, G. & Dejana, E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol. Rev. 84, 869–901 (2004).

    CAS  PubMed  Google Scholar 

  32. Gonzalez-Mariscal, L., Tapia, R. & Chamorro, D. Crosstalk of tight junction components with signaling pathways. Biochim. Biophys. Acta 1778, 729–756 (2008).

    CAS  PubMed  Google Scholar 

  33. Traweger, A. et al. Nuclear Zonula occludens-2 alters gene expression and junctional stability in epithelial and endothelial cells. Differentiation 76, 99–106 (2008).

    CAS  PubMed  Google Scholar 

  34. Lampugnani, M. G., Orsenigo, F., Gagliani, M. C., Tacchetti, C. & Dejana, E. Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments. J. Cell Biol. 174, 593–604 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rudini, N. et al. VE-cadherin is a critical endothelial regulator of TGF-beta signalling. EMBO J. 27, 993–1004 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheng, Y. F. & Kramer, R. H. Human microvascular endothelial cells express integrin-related complexes that mediate adhesion to the extracellular matrix. J. Cell Physiol. 139, 275–286 (1989).

    CAS  PubMed  Google Scholar 

  37. Burridge, K., Fath, K., Kelly, T., Nuckolls, G. & Turner, C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu. Rev. Cell Biol. 4, 487–525 (1988).

    CAS  PubMed  Google Scholar 

  38. Vane, J. R., Anggard, E. E. & Botting, R. M. Regulatory functions of the vascular endothelium. N. Engl. J. Med. 323, 27–36 (1990).

    CAS  PubMed  Google Scholar 

  39. Napoli, C. et al. Nitric oxide and atherosclerosis: an update. Nitric Oxide 15, 265–279 (2006).

    CAS  PubMed  Google Scholar 

  40. Vanhoutte, P. M. Endothelial dysfunction: the first step toward coronary arteriosclerosis. Circ. J. 73, 595–601 (2009).

    CAS  PubMed  Google Scholar 

  41. Wang, G. R., Zhu, Y., Halushka, P. V., Lincoln, T. M. & Mendelsohn, M. E. Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 95, 4888–4893 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Macdonald, P. S., Read, M. A. & Dusting, G. J. Synergistic inhibition of platelet aggregation by endothelium-derived relaxing factor and prostacyclin. Thromb. Res. 49, 437–449 (1988).

    CAS  PubMed  Google Scholar 

  43. Radomski, M. W., Palmer, R. M. & Moncada, S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem. Biophys. Res. Commun. 148, 1482–1489 (1987).

    CAS  PubMed  Google Scholar 

  44. Busse, R. et al. EDHF: bringing the concepts together. Trends Pharmacol. Sci. 23, 374–380 (2002).

    CAS  PubMed  Google Scholar 

  45. Smith, D., Gilbert, M. & Owen, W. G. Tissue plasminogen activator release in vivo in response to vasoactive agents. Blood 66, 835–839 (1985).

    CAS  PubMed  Google Scholar 

  46. Bauer, K. A., Kass, B. L., Beeler, D. L. & Rosenberg, R. D. Detection of protein C activation in humans. J. Clin. Invest. 74, 2033–2041 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nawroth, P., Kisiel, W. & Stern, D. The role of endothelium in the homeostatic balance of haemostasis. Clin. Haematol. 14, 531–546 (1985).

    CAS  PubMed  Google Scholar 

  48. Girard, T. J. et al. Functional significance of the kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 338, 518–520 (1989).

    CAS  PubMed  Google Scholar 

  49. Jones, K. L. et al. Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions. Blood 98, 1456–1463 (2001).

    CAS  PubMed  Google Scholar 

  50. Falati, S. et al. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 107, 535–541 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Simionescu, M., Popov, D. & Sima, A. Endothelial transcytosis in health and disease. Cell Tissue Res. 335, 27–40 (2009).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  53. Brunner, H. et al. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the working group on endothelins and endothelial factors of the European Society of Hypertension. J. Hypertens. 23, 233–246 (2005).

    CAS  PubMed  Google Scholar 

  54. Cai, H. NAD(P)H oxidase-dependent self-propagation of hydrogen peroxide and vascular disease. Circ. Res. 96, 818–822 (2005).

    CAS  PubMed  Google Scholar 

  55. Stabler, T., Kenjale, A., Ham, K., Jelesoff, N. & Allen, J. Potential mechanisms for reduced delivery of nitric oxide to peripheral tissues in diabetes mellitus. Ann. N. Y. Acad. Sci. 1203, 101–106 (2010).

    CAS  PubMed  Google Scholar 

  56. Milsom, A. B. et al. Abnormal metabolic fate of nitric oxide in type I diabetes mellitus. Diabetologia 45, 1515–1522 (2002).

    CAS  PubMed  Google Scholar 

  57. Bunn, H. F. & Briehl, R. W. The interaction of 2, 3-diphosphoglycerate with various human hemoglobins. J. Clin. Invest. 49, 1088–1095 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Tai, S. C., Robb, G. B. & Marsden, P. A. Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel. Arterioscler. Thromb. Vasc. Biol. 24, 405–412 (2004).

    CAS  PubMed  Google Scholar 

  59. Sima, A. V., Stancu, C. S. & Simionescu, M. Vascular endothelium in atherosclerosis. Cell Tissue Res. 335, 191–203 (2009).

    CAS  PubMed  Google Scholar 

  60. Schmidt, T. S. & Alp, N. J. Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin. Sci. (Lond.) 113, 47–63 (2007).

    CAS  Google Scholar 

  61. Civelek, M., Manduchi, E., Riley, R. J., Stoeckert, C. J. Jr & Davies, P. F. Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis. Circ. Cardiovasc. Genet. 4, 243–252 (2011).

    PubMed  PubMed Central  Google Scholar 

  62. Simionescu, M. Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler. Thromb. Vasc. Biol. 27, 266–274 (2007).

    CAS  PubMed  Google Scholar 

  63. Mehrabi, M. R. et al. Accumulation of oxidized LDL in human semilunar valves correlates with coronary atherosclerosis. Cardiovasc. Res. 45, 874–882 (2000).

    CAS  PubMed  Google Scholar 

  64. Williams, K. J. & Tabas, I. Lipoprotein retention—and clues for atheroma regression. Arterioscler. Thromb. Vasc. Biol. 25, 1536–1540 (2005).

    CAS  PubMed  Google Scholar 

  65. Lum, H. & Malik, A. B. Regulation of vascular endothelial barrier function. Am. J. Physiol. 267, L223–L241 (1994).

    CAS  PubMed  Google Scholar 

  66. Dudek, S. M. & Garcia, J. G. Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487–1500 (2001).

    CAS  PubMed  Google Scholar 

  67. Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    CAS  PubMed  Google Scholar 

  68. Kipshidze, N. et al. Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions. J. Am. Coll. Cardiol. 44, 733–739 (2004).

    CAS  PubMed  Google Scholar 

  69. van Beusekom, H. M. et al. Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries. J. Am. Coll. Cardiol. 32, 1109–1117 (1998).

    CAS  PubMed  Google Scholar 

  70. Wenaweser, P. et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J. Am. Coll. Cardiol. 52, 1134–1140 (2008).

    CAS  PubMed  Google Scholar 

  71. Stone, G. W. et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N. Engl. J. Med. 356, 998–1008 (2007).

    CAS  PubMed  Google Scholar 

  72. Kastrati, A. et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N. Engl. J. Med. 356, 1030–1039 (2007).

    CAS  PubMed  Google Scholar 

  73. Kolandaivelu, K. et al. Stent thrombogenicity early in high-risk interventional settings is driven by stent design and deployment and protected by polymer-drug coatings. Circulation 123, 1400–1409 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Nakazawa, G. et al. Coronary responses and differential mechanisms of late stent thrombosis attributed to first-generation sirolimus- and paclitaxel-eluting stents. J. Am. Coll. Cardiol. 57, 390–398 (2011).

    CAS  PubMed  Google Scholar 

  75. Nakazawa, G. et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation 118, 1138–1145 (2008).

    PubMed  Google Scholar 

  76. Finn, A. V. et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 112, 270–278 (2005).

    CAS  PubMed  Google Scholar 

  77. Nakazawa, G. et al. Pathological findings at bifurcation lesions: the impact of flow distribution on atherosclerosis and arterial healing after stent implantation. J. Am. Coll. Cardiol. 55, 1679–1687 (2010).

    PubMed  Google Scholar 

  78. Nakazawa, G. et al. Incidence and predictors of drug-eluting stent fracture in human coronary artery a pathologic analysis. J. Am. Coll. Cardiol. 54, 1924–1931 (2009).

    PubMed  Google Scholar 

  79. Asahara, T. et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ. Res. 85, 221–228 (1999).

    CAS  PubMed  Google Scholar 

  80. Joner, M. et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J. Am. Coll. Cardiol. 52, 333–342 (2008).

    CAS  PubMed  Google Scholar 

  81. Nakazawa, G. et al. Evaluation of polymer-based comparator drug-eluting stents using a rabbit model of iliac artery atherosclerosis. Circ. Cardiovasc. Interv. 4, 38–46 (2011).

    CAS  PubMed  Google Scholar 

  82. Virmani, R., Kolodgie, F. D., Farb, A. & Lafont, A. Drug eluting stents: are human and animal studies comparable? Heart 89, 133–138 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Liu, L. et al. Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 25, 7029–7040 (2006).

    CAS  PubMed  Google Scholar 

  84. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    CAS  PubMed  Google Scholar 

  85. Tsurumi, Y. et al. Reciprocal relation between VEGF and NO in the regulation of endothelial integrity. Nat. Med. 3, 879–886 (1997).

    CAS  PubMed  Google Scholar 

  86. Vinals, F., Chambard, J. C. & Pouyssegur, J. p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J. Biol. Chem. 274, 26776–26782 (1999).

    CAS  PubMed  Google Scholar 

  87. Morales-Ruiz, M. et al. Vascular endothelial growth factor-stimulated actin reorganization and migration of endothelial cells is regulated via the serine/threonine kinase Akt. Circ. Res. 86, 892–896 (2000).

    CAS  PubMed  Google Scholar 

  88. Fosbrink, M., Niculescu, F., Rus, V., Shin, M. L. & Rus, H. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1. J. Biol. Chem. 281, 19009–19018 (2006).

    CAS  PubMed  Google Scholar 

  89. Fulton, D. et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597–601 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat. Med. 8, 1145–1152 (2002).

    CAS  PubMed  Google Scholar 

  91. Fleming, I. & Busse, R. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1–R12 (2003).

    CAS  PubMed  Google Scholar 

  92. Yamamoto, K. & Ando, J. New molecular mechanisms for cardiovascular disease: blood flow sensing mechanism in vascular endothelial cells. J. Pharmacol. Sci. 116, 323–331 (2011).

    CAS  PubMed  Google Scholar 

  93. Togni, M. et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J. Am. Coll. Cardiol. 46, 231–236 (2005).

    CAS  PubMed  Google Scholar 

  94. Hofma, S. H. et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation. Eur. Heart J. 27, 166–170 (2006).

    PubMed  Google Scholar 

  95. Hamilos, M. et al. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for device-specific responses. Circ. Cardiovasc. Interv. 1, 193–200 (2008).

    PubMed  Google Scholar 

  96. van den Heuvel, M. et al. Specific coronary drug-eluting stents interfere with distal microvascular function after single stent implantation in pigs. JACC Cardiovasc. Interv. 3, 723–730 (2010).

    PubMed  Google Scholar 

  97. Pendyala, L. K. et al. The first-generation drug-eluting stents and coronary endothelial dysfunction. JACC Cardiovasc. Interv. 2, 1169–1177 (2009).

    PubMed  Google Scholar 

  98. Sahler, L. G. et al. Comparison of vasa vasorum after intravascular stent placement with sirolimis drug-eluting and bare metal stents. J. Med. Imaging Radiat. Oncol. 52, 570–575 (2008).

    CAS  PubMed  Google Scholar 

  99. van Beusekom, H. M. et al. Endothelial function rather than endothelial restoration is altered in paclitaxel- as compared to bare metal-, sirolimus and tacrolimus-eluting stents. EuroIntervention 6, 117–125 (2010).

    PubMed  Google Scholar 

  100. Kim, J. W. et al. A prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent: differential recovery of coronary endothelial dysfunction. J. Am. Coll. Cardiol. 53, 1653–1659 (2009).

    CAS  PubMed  Google Scholar 

  101. Shin, D. I. et al. Long-term coronary endothelial function after zotarolimus-eluting stent implantation. A 9 month comparison between zotarolimus-eluting and sirolimus-eluting stents. Int. Heart J. 49, 639–652 (2008).

    PubMed  Google Scholar 

  102. Lowe, H. C., Narula, J., Fujimoto, J. G. & Jang, I. K. Intracoronary optical diagnostics current status, limitations, and potential. JACC Cardiovasc. Interv. 4, 1257–1270 (2011).

    PubMed  Google Scholar 

  103. Fujii, K. et al. Endothelium-dependent coronary vasomotor response and neointimal coverage of zotarolimus-eluting stents 3 months after implantation. Heart 97, 977–982 (2011).

    PubMed  Google Scholar 

  104. Liu, L. et al. Imaging the subcellular structure of human coronary atherosclerosis using micro-optical coherence tomography. Nat. Med. 17, 1010–1014 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Davies, P. F. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat. Clin. Pract. Cardiovasc. Med. 6, 16–26 (2009).

    CAS  PubMed  Google Scholar 

  106. Lam, C. F. et al. Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin. Am. J. Physiol. Heart Circ. Physiol. 290, H786–H793 (2006).

    CAS  PubMed  Google Scholar 

  107. Go, Y. M. et al. Protein kinase B/Akt activates c-Jun NH(2)-terminal kinase by increasing NO production in response to shear stress. J. Appl. Physiol. 91, 1574–1581 (2001).

    CAS  PubMed  Google Scholar 

  108. Ziegler, T., Bouzourene, K., Harrison, V. J., Brunner, H. R. & Hayoz, D. Influence of oscillatory and unidirectional flow environments on the expression of endothelin and nitric oxide synthase in cultured endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 686–692 (1998).

    CAS  PubMed  Google Scholar 

  109. Qiu, Y. & Tarbell, J. M. Interaction between wall shear stress and circumferential strain affects endothelial cell biochemical production. J. Vasc. Res. 37, 147–157 (2000).

    CAS  PubMed  Google Scholar 

  110. Malek, A. M., Alper, S. L. & Izumo, S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 282, 2035–2042 (1999).

    CAS  PubMed  Google Scholar 

  111. Traub, O. & Berk, B. C. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler. Thromb. Vasc. Biol. 18, 677–685 (1998).

    CAS  PubMed  Google Scholar 

  112. Papadaki, M. et al. Differential regulation of protease activated receptor-1 and tissue plasminogen activator expression by shear stress in vascular smooth muscle cells. Circ. Res. 83, 1027–1034 (1998).

    CAS  PubMed  Google Scholar 

  113. Papaharalambus, C. A. & Griendling, K. K. Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury. Trends Cardiovasc. Med. 17, 48–54 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Nakazawa, G. et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J. Am. Coll. Cardiol. 57, 1314–1322 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Tabas, I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler. Thromb. Vasc. Biol. 25, 2255–2264 (2005).

    CAS  PubMed  Google Scholar 

  116. Tulenko, T. N., Chen, M., Mason, P. E. & Mason, R. P. Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J. Lipid Res. 39, 947–956 (1998).

    CAS  PubMed  Google Scholar 

  117. Farb, A., Shroff, S., John, M., Sweet, W. & Virmani, R. Late arterial responses (6 and 12 months) after (32)P β-emitting stent placement: sustained intimal suppression with incomplete healing. Circulation 103, 1912–1919 (2001).

    CAS  PubMed  Google Scholar 

  118. Jeremias, A. et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 109, 1930–1932 (2004).

    PubMed  Google Scholar 

  119. Kushner, F. G. et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 120, 2271–2306 (2009).

    PubMed  Google Scholar 

  120. Park, S. J. et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N. Engl. J. Med. 362, 1374–1382 (2010).

    CAS  PubMed  Google Scholar 

  121. Valgimigli, M. Assessing the most appropriate duration of dual antiplatelet therapy after coronary stenting: the PRODIGY study. Hot Line III—Acute coronary syndromes. European Society of Cardiology [online], (2011).

    Google Scholar 

  122. Gwon, H. C. et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the efficacy of xience/promus versus cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study. Circulation 125, 505–513 (2012).

    CAS  PubMed  Google Scholar 

  123. Mauri, L. et al. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent or bare metal stent placement for the treatment of coronary artery lesions. Am. Heart J. 160, 1035–1041 (2010).

    CAS  PubMed  Google Scholar 

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Acknowledgements

CVPath Institute Inc., Gaithersburg, USA provided full support for this work. F. Otsuka is supported by a research fellowship from the Uehara Memorial Foundation, Tokyo, Japan.

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Authors and Affiliations

  1. CVPath Institute Inc., 19 Firstfield Road, Gaithersburg, 20878, MD, USA

    Fumiyuki Otsuka, Saami K. Yazdani, Masataka Nakano, Frank D. Kolodgie & Renu Virmani

  2. Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, 30322, GA, USA

    Aloke V. Finn

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  1. Fumiyuki Otsuka
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Contributions

F. Otsuka, A. V. Finn, S. K. Yazdani and R. Virmani researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission. M. Nakano and F. D. Kolodgie researched data for the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Renu Virmani.

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Competing interests

A. V. Finn has received grant or research support from Boston Scientific and Medtronic. R. Virmani has been a consultant for Abbott Vascular, Arsenal Medical, Atrium Medical, Biosensors International, GlaxoSmithKline, Lutonix, Medtronic Arterial Vascular Engineering and W. L. Gore. The other authors declare no competing interests.

Supplementary information

Supplementary Figure 1

Histologic sections from a patient with an occluded sirolimus-eluting stent. (DOC 1211 kb)

Supplementary Figure 2

The proposed role of mTOR in vascular repair. (PDF 85 kb)

Supplementary Figure 3

Cumulative incidence of neoatherosclerosis with time after implantation of BMS, PES, and SES. (DOC 173 kb)

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Otsuka, F., Finn, A., Yazdani, S. et al. The importance of the endothelium in atherothrombosis and coronary stenting. Nat Rev Cardiol 9, 439–453 (2012). https://doi.org/10.1038/nrcardio.2012.64

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