Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening

Department of Medicine, (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.

OBJECTIVES: This study sought to test the hypothesis that direct gene transfer of an endothelial cell mitogen could passivate metallic stents by accelerating endothelialization of the prosthesis. BACKGROUND: Thrombosis and restenosis comprise the principal clinical manifestations of compromised biocompatibility of endovascular stents. Previous studies have demonstrated that endothelial recovery at sites of balloon injury is a critical determinant of consequent intimal thickening and mural thrombus. We therefore investigated the potential for an endothelial cell mitogen delivered as plasmid DNA to optimize stent biocompatibility. METHODS: Naked plasmid DNA encoding vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) (phVEGF165) was delivered locally using a hydrogel-coated balloon angioplasty catheter to 16 rabbit iliac arteries in which metallic stents had been placed at the site of balloon injury; the contralateral iliac artery of each rabbit was balloon injured and stented but not transfected. RESULTS: Stent endothelialization was accelerated by phVEGF165 gene transfer (87.38 +/- 5.06% vs. 33.13 +/- 9.73% [mean +/- SEM] of the planimetered stent surface in the treated vs. contralateral limb, p = 0.005). This was associated with a significant reduction in mural thrombus (3.7 +/- 2.4% vs. 32.7 +/- 9.7%, p = 0.01) at day 7 and intimal thickening (maximal intimal area 0.61 +/- 0.09 vs. 1.44 +/- 0.12 mm2, p < 0.0001) at day 28. No benefit was observed from pCMV-luciferase in 14 similarly instrumented control rabbits. CONCLUSIONS: These findings indicate that arterial gene transfer of naked plasmid DNA encoding for an endothelial cell mitogen may successfully passivate endovascular stents by accelerating stent endothelialization, thereby reducing in-stent thrombus and obstruction due to intimal thickening.

This article has been cited by other articles:

				G. E. Kochiadakis, M. E. Marketou, D. Panutsopulos, D. A. Arfanakis, E. I. Skalidis, N. E. Igoumenidis, M. I. Hamilos, G. Sourvinos, G. Chlouverakis, D. Spandidos, et al. Vascular endothelial growth factor protein levels and gene expression in peripheral monocytes after stenting: a randomized comparative study of sirolimus: eluting and bare metal stents Eur. Heart J., March 2, 2008; 29(6): 733 - 740. [Abstract] [Full Text] [PDF]

				M. Lahtinen, P. Blomberg, G. Baliulis, F. Carlsson, H. Khamis, and V. Zemgulis In vivo h-VEGF165 gene transfer improves early endothelialisation and patency in synthetic vascular grafts Eur. J. Cardiothorac. Surg., March 1, 2007; 31(3): 383 - 390. [Abstract] [Full Text] [PDF]

				A. N. Cheema, T. Hong, N. Nili, A. Segev, J. G. Moffat, K. E. Lipson, A. R. Howlett, D. W. Holdsworth, M. J. Cole, B. Qiang, et al. Adventitial Microvessel Formation After Coronary Stenting and the Effects of SU11218, a Tyrosine Kinase Inhibitor J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1067 - 1075. [Abstract] [Full Text] [PDF]

				C.-H. Lee, H.-C. Tan, and Y.-T. Lim Update on Drug-Eluting Stents for Prevention of Restenosis Asian Cardiovasc Thorac Ann, February 1, 2006; 14(1): 75 - 82. [Abstract] [Full Text] [PDF]

				S. Susen, K. Sautiere, F. Mouquet, F. Cuilleret, A. Chmait, E. P. McFadden, B. Hennache, F. Richard, P. de Groote, J.-M. Lablanche, et al. Serum hepatocyte growth factor levels predict long-term clinical outcome after percutaneous coronary revascularization Eur. Heart J., November 2, 2005; 26(22): 2387 - 2395. [Abstract] [Full Text] [PDF]

				J. Dulak, S. P Schwarzacher, R. H Zwick, H. Alber, G. Millonig, C. Weiss, H. Hugel, M. Frick, A. Jozkowicz, O. Pachinger, et al. Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits Vascular Medicine, November 1, 2005; 10(4): 285 - 291. [Abstract] [PDF]

				M. A. Costa and D. I. Simon Molecular Basis of Restenosis and Drug-Eluting Stents Circulation, May 3, 2005; 111(17): 2257 - 2273. [Full Text] [PDF]

				N. Kipshidze, G. Dangas, M. Tsapenko, J. Moses, M. B. Leon, M. Kutryk, and P. Serruys Role of the endothelium in modulating neointimal formation: Vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions J. Am. Coll. Cardiol., August 18, 2004; 44(4): 733 - 739. [Abstract] [Full Text] [PDF]

				D. H. Walter, M. Cejna, L. Diaz-Sandoval, S. Willis, L. Kirkwood, P. W. Stratford, A. B. Tietz, R. Kirchmair, M. Silver, C. Curry, et al. Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents: An Alternative Strategy for Inhibition of Restenosis Circulation, July 6, 2004; 110(1): 36 - 45. [Abstract] [Full Text] [PDF]

				Y. Numaguchi, K. Okumura, M. Harada, K. Naruse, M. Yamada, H. Osanai, H. Matsui, M. Ito, and T. Murohara Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries Cardiovasc Res, January 1, 2004; 61(1): 177 - 185. [Abstract] [Full Text] [PDF]

				D. H. Walter, K. Rittig, F. H. Bahlmann, R. Kirchmair, M. Silver, T. Murayama, H. Nishimura, D. W. Losordo, T. Asahara, and J. M. Isner Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Circulation, June 25, 2002; 105(25): 3017 - 3024. [Abstract] [Full Text] [PDF]

				K. B. Lemstrom, R. Krebs, A. I. Nykanen, J. M. Tikkanen, R. K. Sihvola, E. M. Aaltola, P. J. Hayry, J. Wood, K. Alitalo, S. Yla-Herttuala, et al. Vascular Endothelial Growth Factor Enhances Cardiac Allograft Arteriosclerosis Circulation, May 28, 2002; 105(21): 2524 - 2530. [Abstract] [Full Text] [PDF]

				S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]

				J. M. Isner, P. R. Vale, J. F. Symes, and D. W. Losordo Assessment of Risks Associated With Cardiovascular Gene Therapy in Human Subjects Circ. Res., August 31, 2001; 89(5): 389 - 400. [Abstract] [Full Text] [PDF]

				D. W. Losordo and J. M. Isner Vascular endothelial growth factor-induced angiogenesis: crouching tiger or hidden dragon? J. Am. Coll. Cardiol., June 15, 2001; 37(8): 2131 - 2135. [Full Text] [PDF]

				S. L. Meyerson, C. L. Skelly, M. A. Curi, and L. B. Schwartz Gene Therapy for Cardiovascular Disease Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2000; 4(4): 289 - 300. [Abstract] [PDF]

				N. Kipshidze, J. J. Ferguson III, M. H. Keelan Jr., H. Sahota, R. Komorowski, L. R. Shankar, P. S. Chawla, C. C. Haudenschild, V. Nikolaychik, and J. W. Moses Endoluminal reconstruction of the arterial wall with endothelial cell/glue matrix reduces restenosis in an atherosclerotic rabbit J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1396 - 1403. [Abstract] [Full Text] [PDF]

				I. Zachary, A. Mathur, S. Yla-Herttuala, and J. Martin Vascular Protection : A Novel Nonangiogenic Cardiovascular Role for Vascular Endothelial Growth Factor Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1512 - 1520. [Abstract] [Full Text] [PDF]

				J Gunn and D Cumberland Stent coatings and local drug delivery. State of the art Eur. Heart J., December 1, 1999; 20(23): 1693 - 1700. [PDF]

				P. Sinnaeve, O. Varenne, D. Collen, and S. Janssens Gene therapy in the cardiovascular system: an update Cardiovasc Res, December 1, 1999; 44(3): 498 - 506. [Abstract] [Full Text] [PDF]

				J. M. Isner Cancer and Atherosclerosis : The Broad Mandate of Angiogenesis Circulation, April 6, 1999; 99(13): 1653 - 1655. [Full Text] [PDF]

				O. F. Bertrand, R. Sipehia, R. Mongrain, J. Rodes, J.-C. Tardif, L. Bilodeau, G. Cote, and M. G. Bourassa Biocompatibility aspects of new stent technology J. Am. Coll. Cardiol., September 1, 1998; 32(3): 562 - 571. [Abstract] [Full Text] [PDF]

				E. Van Belle, C. Bauters, T. Asahara, and J. M. Isner Endothelial regrowth after arterial injury: from vascular repair to therapeutics Cardiovasc Res, April 1, 1998; 38(1): 54 - 68. [Full Text] [PDF]

				S. Baek and K. L. March Gene Therapy for Restenosis : Getting Nearer the Heart of the Matter Circ. Res., February 23, 1998; 82(3): 295 - 305. [Abstract] [Full Text] [PDF]

				S. C. FRANCIS, M. K. RAIZADA, A. A. MANGI, L. G. MELO, V. J. DZAU, P. R. VALE, J. M. ISNER, D. W. LOSORDO, J. CHAO, M. J. KATOVICH, et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics, December 21, 2001; 7(2): 79 - 94. [Abstract] [Full Text] [PDF]