Abstract
The putative effects of changes in mean strain and cyclic strain amplitude on vascular smooth muscle cell (vSMC) growth (proliferation and apoptosis) were examined. Subsequently, a quantitative measure of vSMC growth was obtained to determine the prolonged effect of changes in mechanical burden following bare-metal stent (BMS) and sirolimus drug-eluting stent (DES) deployment in vitro. Bovine aortic vSMCs were exposed to prolonged cyclic strain using a FlexercellTM Tension system and a novel SylgardTM phantom vessel following stent implantation before the level of vSMC proliferation and apoptosis was assessed by FACS analysis, cell counting, and immunocytochemistry. Physiological cyclic strain (5%) decreased vSMC proliferation and increased apoptosis in a temporal manner. There was no significant difference in cell growth following exposure to varying mean strains with similar amplitude. In contrast, exposure to varying strain amplitudes with similar mean strains resulted in significant differences in cell proliferation and apoptosis. In parallel studies, the level of vSMC proliferation and cell survival was significantly increased within low amplitude, high mean strain regions of a phantom vessel following BMS implantation when compared to regions of higher strain amplitude upstream and downstream of the stent, respectively. Moreover, the level of vSMC growth within the stented region was significantly attenuated following implantation of a sirolimus-coated DES independent of significant changes in cell survival. Cyclic strain amplitude is an important regulator of vSMC growth capacity within a stent and is a target for inhibition using a sirolimus-coated DES.
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Acampora KB, Nagatomi J, Langan EM, LaBerge M (2010) Increased Synthetic Phenotype Behavior of Smooth Muscle Cells in Response to In Vitro Balloon Angioplasty Injury Model. Ann Vasc Surg 24: 116–126
Babapulle MN, Eisenberg MJ (2002) Coated scents for the prevention of restenosis: part II. Circulation 106: 2859–2866
Balcells M, Martorell J, Olive C, Santacana M, Chitalia V, Cardoso AA, Edelman ER (2010) Smooth muscle cells orchestrate the endothelial cell response to flow and injury. Circulation 121: 2192–2199
Bayer IM, Adamson SL, Langille BL (1999) Atrophic remodeling of the artery-cuffed artery. Arterioscler Thromb Vasc Biol 19: 1499–1505
Bedoya J, Meyer CA, Timmins LH, Moreno MR, Moore JE Jr. (2006) Effects of stent design parameters on normal artery wall mechanics. J Biomech Eng 128(5): 757–765
Berry JL, Manoach E, Mekkaoui C, Rolland PH, Moore JE Jr., Rachev A (2002) Hemodynamics and wall mechanics of a compliance matching stent: in vitro and in vivo analysis. J Vasc Interv Radiol 13: 97–105
Cappadona C, Redmond EM, Theodorakis NG, McKillop IH, Hendrickson R, Chhabra A, Sitzmann JV, Cahill PA (1999) Phenotype dictates the growth response of vascular smooth muscle cells to pulse pressure in vitro. Exp Cell Res 250: 174–186
Colombo A, Cahill PA, Lally C (2008) An analysis of the strain field in biaxial Flexcell membranes for different waveforms and frequencies. Proc Inst Mech Eng H 222: 1235–1245
Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr., Spanos V, Louvard Y, Desmedt B, Di Mario C, Leon MB (2004) Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 109: 1244–1249
Colombo A, Zahedmanesh H, Toner DM, Cahill PA, Lally C (2010) A method to develop mock arteries suitable for cell seeding and in-vitro cell culture experiments. J Mech Behav Biomed Mater 3: 470–477
Duraiswamy N, Schoephoerster RT, Moreno MR, Moore JE (2007) Stented artery flow patterns and their effects on the artery wall. Annu Rev Fluid Mech 39: 357–382
Early M, Lally C, Prendergast PJ, Kelly DJ (2009) Stresses in peripheral arteries following stent placement: a finite element analysis. Comput Method Biomech Biomed Eng 12: 25–33
Ekstrand J, Razuvaev A, Folkersen L, Roy J, Hedin U (2010) Tissue factor pathway inhibitor-2 is induced by fluid shear stress in vascular smooth muscle cells and affects cell proliferation and survival. J Vasc Surg 52: 167–175
Gao W, Ferguson G, Connell P, Walshe T, Murphy R, Birney YA, O’Brien C, Cahill PA (2007) High glucose concentrations alter hypoxia-induced control of vascular smooth muscle cell growth via a HIF-1 alpha-dependent pathway. J Mol Cell Cardiol 42: 609–619
Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10: 53–62
Holmes DR Jr., Williams DO (2008) Catheter-based treatment of coronary artery disease: past, present, and future. Circ Cardiovasc Interv 1: 60–73
Kastrati A, Mehilli J, Dirschinger J, Dotzer F, Schuhlen H, Neumann FJ, Fleckenstein M, Pfafferott C, Seyfarth M, Schomig A (2001) Intracoronary stenting and angiographic results—Strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation 103: 2816–2821
Kastrati A, Mehilli J, Dirschinger J, Pache J, Ulm K, Schuhlen H, Seyfarth M, Schmitt C, Blasini R, Neumann FJ, Schomig A (2001) Restenosis after coronary placement of various stent types. Am J Cardiol 87: 34–39
Kastrati A, Schomig A, Dirschinger J, Mehilli J, Dotzer F, von Welser N, Neumann FJ (2000) A randomized trial comparing stenting with balloon angioplasty in small vessels in patients with symptomatic coronary artery disease. ISAR-SMART Study Investigators. Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries. Circulation 102: 2593–2598
Kukreja N, Onuma Y, Daemen J, Serruys PW (2008) The future of drug-eluting stents. Pharmacol Res 57(3): 171–180
Lally C, Dolan F, Prendergast PJ (2005) Cardiovascular stent design and vessel stresses: a finite element analysis. J Biomech 38: 1574–1581
LaDisa JF Jr., Olson LE, Molthen RC, Hettrick DA, Pratt PF, Hardel MD, Kersten JR, Warltier DC, Pagel PS (2005) Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries. Am J Physiol Heart Circ Physiol 288(5): H2465–75
Liu SQ, Tang D, Tieche C, Alkema PK (2003) Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: mediation by gradient of cell density. Am J Physiol Heart Circ Physiol 285: H1072–H1080
Makaryus AN, Lefkowitz L, Lee ADK (2007) Coronary artery stent fracture. Int J Cardiovasc Imag 23: 305–309
Morrow D, Scheller A, Birney YA, Sweeney C, Guha S, Cummins PM, Murphy R, Walls D, Redmond EM, Cahill PA (2005) Notch-mediated CBF-1/RBP-J{kappa}-dependent regulation of human vascular smooth muscle cell phenotype in vitro. Am J Physiol Cell Physiol 289: C1188–C1196
Morrow D, Sweeney C, Birney YA, Cummins PM, Walls D, Redmond EM, Cahill PA (2005) Cyclic strain inhibits notch receptor signaling in vascular smooth muscle cells in vitro. Circ Res 96: 567–575
Morrow D, Sweeney C, Birney YA, Guha S, Collins N, Cummins PM, Murphy R, Walls D, Redmond EM, Cahill PA (2007) Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo. Am J Physiol Cell Physiol 292: C488–496
Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C, Investigators B-L (2006) Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents—an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 48: 2584–2591
Pfisterer ME (2008) Late Stent thrombosis after drug-eluting stent implantation for acute myocardial infarction—a new red flag is raised. Circulation 118: 1117–1119
Punchard MA, O’Cearbhaill ED, Mackle JN, McHugh PE, Smith TJ, Stenson-Cox C, Barron V (2009) Evaluation of human endothelial cells post stent deployment in a cardiovascular simulator in vitro. Ann Biomed Eng 37: 1322–1330
Rolland PH, Mekkaoui C, Vidal V, Berry JL, Moore JE, Moreno M, Amabile P, Bartoli JM (2004) Compliance matching stent placement in the carotid artery of the swine promotes optimal blood flow and attenuates restenosis. Eur J Vasc Endovasc Surg 28: 431–438
Salacinski HJ, Goldner S, Giudiceandrea A, Hamilton G, Seifalian AM, Edwards A, Carson RJ (2001) The mechanical behavior of vascular grafts: a review. J Biomater Appl 15: 241–278
Sketch MH Jr., Ball M, Rutherford B, Popma JJ, Russell C, Kereiakes DJ (2005) Evaluation of the Medtronic (Driver) cobalt-chromium alloy coronary stent system. Am J Cardiol 95: 1812
Stone GW, Ellis SG, Colombo A, Dawkins KD, Grube E, Cutlip DE, Friedman M, Baim DS, Koglin J (2007) Offsetting impact of thrombosis and restenosis on the occurrence of death and myocardial infarction after paclitaxel-eluting and bare metal stent implantation. Circulation 115: 2842–2847
Timmins LH, Miller MW, Clubb FJ Jr., Moore JE Jr. (2011) Increased artery wall stress post-stenting leads to greater intimal thickening. Lab Invest 91: 955–967
van Beusekom HM, Whelan DM, Hofma SH, Krabbendam SC, van Hinsbergh VW, Verdouw PD, van der Giessen WJ (1998) Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries. J Am Coll Cardiol 32: 1109–1117
Vernhet H, Demaria R, Juan JM, Oliva-Lauraire MC, Senac JP, Dauzat M (2001) Changes in wall mechanics after endovascular stenting in the rabbit aorta: comparison of three stent designs. Am J Roentgenol 176: 803–807
Vernhet H, Demaria R, Perez-Martin A, Juan JM, Oliva-Lauraire MC, Marty-Double C, Senac JP, Dauzat M (2003) Wall mechanics of the stented rabbit aorta: long-term study and correlation with histological findings. J Endovasc Ther 10: 577–584
Wedding KL, Draney MT, Herfkens RJ, Zarins CK, Taylor CA, Pelc NJ (2002) Measurement of vessel wall strain using cine phase contrast MRI. J Magn Reson Imaging 15: 418–428
Wentzel JJ, Whelan MD, van der Giessen WJ, van Beusekom HM, Andhyiswara I, Serruys PW, Slager CJ, Krams R (2000) Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution. J Biomech 33(10): 1287–1295
Wernig F, Mayr M, Xu QB (2003) Mechanical stretch-induced apoptosis in smooth muscle cells is mediated by beta(1)-integrin signaling pathways. Hypertension 41: 903–911
Wessely R (2010) New drug-eluting stent concepts. Nat Rev Cardiol 7: 194–203
Zahedmanesh H, Lally C (2009) Determination of the influence of stent strut thickness using the finite element method: implications for vascular injury and in-stent restenosis. Med Biol Eng Comput 47: 385–393
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Colombo, A., Guha, S., Mackle, J.N. et al. Cyclic strain amplitude dictates the growth response of vascular smooth muscle cells in vitro: role in in-stent restenosis and inhibition with a sirolimus drug-eluting stent. Biomech Model Mechanobiol 12, 671–683 (2013). https://doi.org/10.1007/s10237-012-0433-4
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DOI: https://doi.org/10.1007/s10237-012-0433-4