Inhibition of plaque neovascularization and intimal hyperplasia by specific targeting vascular endothelial growth factor with bevacizumab-eluting stent: An experimental study


      Neovascularization is associated with destabilization of atheromatic plaques. Increased expression of vascular endothelial growth factor (VEGF) is important in the process of neovascularization. We assessed the effect of bevacizumab, a monoclonal antibody specific for VEGF, on neovascularization. We used 12 New Zealand rabbits under atherogenic diet for 3 weeks. We immersed a phosphorycholine coated stent into a solution of 4 ml bevacizumab according to previous studies. Twelve eluting stents and 12 non-eluting stents were implanted in the middle segment of the rabbit's iliac arteries. Follow-up angiography was performed at 4 weeks and tissues were obtained for histological analysis. The procedure of stent loading with bevacizumab and stent implantation was successful. There was no difference in angiographic measurements before, after implantation and at follow-up between the two groups. mean neointimal thickness (0.09 ± 0.02 versus 0.12 ± 0.02 mm, p < 0.01), and mean neointimal area (1.08 ± 0.09 versus 1.20 ± 0.12 mm2, p < 0.01) were less in the bevacizumab treated segments. bevacizumab-treated arterial segments demonstrated significantly decreased microvessel density compared with the control group (1.69 ± 0.06 CI: 1.65–1.73 versus 15.68 ± 0.56 CI: 15.32–16.04 vessels per mm2, p < 0.001) and vegf expression was decreased in the media and adventitia of bevacizumab group. Endothelialization, inflammation and injury scores were similar between the two groups. These results suggest that bevacizumab-eluting stent implantation in rabbit iliac arteries is safe, and inhibits neovascularization without affecting the endothelialization.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kumamoto M.
        • Nakashima Y.
        • Sueishi K.
        Intimal neovascularization in human coronary atherosclerosis.
        Hum Pathol. 1995; 26: 450-456
        • Barger A.C.
        • Beeuwkes 3rd, R.
        • Lainey L.L.
        • Silverman K.J.
        Hypothesis: vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis.
        N Engl J Med. 1984; 310: 175-177
        • Wilson S.H.
        • Herrmann J.
        • Lerman L.O.
        • et al.
        Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering.
        Circulation. 2002; 105: 415-418
        • Moulton K.S.
        • Vakili K.
        • Zurakowski D.
        • et al.
        Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis.
        Proc Natl Acad Sci USA. 2003; 100: 4736-4741
        • Stefanadis C.
        • Vlachopoulos C.
        • Karayannacos P.
        • et al.
        Effect of vasa vasorum flow on structure and function of the aorta in experimental animals.
        Circulation. 1995; 91: 2669-2678
        • Stefanadis C.I.
        • Karayannacos P.E.
        • Boudoulas H.K.
        • et al.
        Medial necrosis and acute alterations in aortic distensibility following removal of the vasa vasorum of canine ascending aorta.
        Cardiovasc Res. 1993; 27: 951-956
        • Zhu X.Y.
        • Rodriguez-Porcel M.
        • Bentley M.D.
        • et al.
        Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia.
        Circulation. 2004; 109: 2109-2115
        • Ganaha F.
        • Kao E.Y.
        • Wong H.
        • et al.
        Stent-based controlled release of intravascular angiostatin to limit plaque progression and in-stent restenosis.
        J Vasc Interv Radiol. 2004; 15: 601-608
        • Rodriguez J.A.
        • Nespereira B.
        • Perez-Ilzarbe M.
        • Eguinoa E.
        • Paramo J.A.
        Vitamins C and E prevent endothelial VEGF and VEGFR-2 overexpression induced by porcine hypercholesterolemic LDL.
        Cardiovasc Res. 2005; 65: 665-673
        • Kerwin W.
        • Hooker A.
        • Spilker M.
        • et al.
        Quantitative magnetic resonance imaging analysis of neovasculature volume in carotid atherosclerotic plaque.
        Circulation. 2003; 107: 851-856
        • O’Malley S.M.
        • Vavuranakis M.
        • Naghavi M.
        • Kakadiaris I.A.
        Intravascular ultrasound-based imaging of vasa vasorum for the detection of vulnerable atherosclerotic plaque.
        Med Image Comput Comput Assist Interv Int Conf Med Image Comput Comput Assist Interv. 2005; 8: 343-351
        • Bhardwaj S.
        • Roy H.
        • Heikura T.
        • Yla-Herttuala S.
        VEGF-A, VEGF-D and VEGF-D(DeltaNDeltaC) induced intimal hyperplasia in carotid arteries.
        Eur J Clin Invest. 2005; 35: 669-676
        • Celletti F.L.
        • Waugh J.M.
        • Amabile P.G.
        • et al.
        Vascular endothelial growth factor enhances atherosclerotic plaque progression.
        Nat Med. 2001; 7: 425-429
        • Hurwitz H.
        • Fehrenbacher L.
        • Novotny W.
        • et al.
        Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
        N Engl J Med. 2004; 350: 2335-2342
        • Yang J.
        • Hawworth L.
        • Sherry R.
        A randomised trial of bevacizumab, an antivascular endothelial growth antibody for metastatic renal cancer.
        N Engl J Med. 2003; 349: 427-434
        • Abizaid A.
        • Albertal M.
        • Costa M.A.
        • et al.
        First human experience with the 17-beta-estradiol-eluting stent: the Estrogen And Stents To Eliminate Restenosis (EASTER) trial.
        J Am Coll Cardiol. 2004; 43: 1118-1121
        • New G.
        • Moses J.W.
        • Roubin G.S.
        • et al.
        Estrogen-eluting, phosphorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model.
        Catheter Cardiovasc Interv. 2002; 57: 266-271
        • Kim W.
        • Jeong M.H.
        • Cha K.S.
        • et al.
        Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model.
        Circ J. 2005; 69: 101-106
        • Farb A.
        • Tang A.L.
        • Shroff S.
        • Sweet W.
        • Virmani R.
        Neointimal responses 3 months after (32)P beta-emitting stent placement.
        Int J Radiat Oncol Biol Phys. 2000; 48: 889-898
        • Hehrlein C.
        • Kaiser S.
        • Riessen R.
        • et al.
        External beam radiation after stent implantation increases neointimal hyperplasia by augmenting smooth muscle cell proliferation and extracellular matrix accumulation.
        J Am Coll Cardiol. 1999; 34: 561-566
        • Daruwalla J.
        • Nikfarjam M.
        • Malcontenti-Wilson C.
        • Muralidharan V.
        • Christophi C.
        Effect of thalidomide on colorectal cancer liver metastases in CBA mice.
        J Surg Oncol. 2005; 91: 134-140
        • Herrmann J.
        • Lerman L.O.
        • Rodriguez-Porcel M.
        • et al.
        Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia.
        Cardiovasc Res. 2001; 51: 762-766
        • Moreno P.R.
        • Purushothaman K.R.
        • Sirol M.
        • Levy A.P.
        • Fuster V.
        Neovascularization in human atherosclerosis.
        Circulation. 2006; 113: 2245-2252
        • Fleiner M.
        • Kummer M.
        • Mirlacher M.
        • et al.
        Arterial neovascularization and inflammation in vulnerable patients: early and late signs of symptomatic atherosclerosis.
        Circulation. 2004; 110: 2843-2850
        • Moreno P.R.
        • Purushothaman K.R.
        • Fuster V.
        • et al.
        Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability.
        Circulation. 2004; 110: 2032-2038
        • Stefanadis C.
        • Toutouzas K.
        • Stefanadi E.
        • et al.
        First experimental application of bevacizumab-eluting PC coated stent for inhibition of vasa vasorum of atherosclerotic plaque: angiographic results in a rabbit atheromatic model.
        Hellenic J Cardiol. 2006; 47: 7-10
        • Kipshidze N.N.
        • Iversen P.
        • Kim H.S.
        • et al.
        Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model.
        Catheter Cardiovasc Interv. 2004; 61: 518-527
        • Shah M.A.
        • Ilson D.
        • Kelsen D.P.
        Thromboembolic events in gastric cancer: high incidence in patients receiving irinotecan- and bevacizumab-based therapy.
        J Clin Oncol. 2005; 23: 2574-2576
        • Lewis A.L.
        • Willis S.L.
        • Small S.A.
        • et al.
        Drug loading and elution from a phosphorylcholine polymer-coated coronary stent does not affect long-term stability of the coating in vivo.
        Biomed Mater Eng. 2004; 14: 355-370
        • Moses J.W.
        • Leon M.B.
        • Popma J.J.
        • et al.
        Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.
        N Engl J Med. 2003; 349: 1315-1323
        • Stone G.W.
        • Ellis S.G.
        • Cox D.A.
        • et al.
        A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.
        N Engl J Med. 2004; 350: 221-231
        • Kabbinavar F.
        • Hurwitz H.I.
        • Fehrenbacher L.
        • et al.
        Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer.
        J Clin Oncol. 2003; 21: 60-65
        • Midgley R.
        • Kerr D.
        Bevacizumab-current status and future directions.
        Ann Oncol. 2005; 16: 999-1004