Endothelial Recovery
2003; Lippincott Williams & Wilkins; Volume: 107; Issue: 21 Linguagem: Inglês
10.1161/01.cir.0000071083.31270.c3
ISSN1524-4539
AutoresDouglas W. Losordo, Jeffrey M. Isner, Larry J. Díaz‐Sandoval,
Tópico(s)Nuclear Receptors and Signaling
ResumoHomeCirculationVol. 107, No. 21Endothelial Recovery Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBEndothelial RecoveryThe Next Target in Restenosis Prevention Douglas W. Losordo, MD, Jeffrey M. Isner, MD and Larry J. Diaz-Sandoval, MD Douglas W. LosordoDouglas W. Losordo From the Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass. , Jeffrey M. IsnerJeffrey M. Isner From the Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass. and Larry J. Diaz-SandovalLarry J. Diaz-Sandoval From the Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass. Originally published3 Jun 2003https://doi.org/10.1161/01.CIR.0000071083.31270.C3Circulation. 2003;107:2635–2637In this world there are only two tragedies. One is not getting what one wants and the other is getting it.— —Oscar WildeBy most accounts, the field of interventional cardiology appears to have achieved one of its most elusive milestones, the virtual eradication of restenosis. In the present issue of Circulation, however, Hedman and colleagues1 report the results of a pilot study of gene therapy with vascular endothelial growth factor (VEGF) for restenosis prevention. Are these authors attempting to develop a treatment for a disease that no longer exists? Or is it possible that the mounting exuberance anticipating the release of drug-eluting stents is ignoring a major liability of these otherwise promising therapies?See p 2677Percutaneous transluminal coronary angioplasty (PTCA) has been used to relieve symptoms and ischemia in patients with coronary disease for more than 2 decades. Despite an initial success rate of well over 90%, coronary arterial renarrowing of initially revascularized sites, or restenosis, constitutes the principal major complication of PTCA.The pathogenesis of restenosis has classically been regarded as involving either reactive constriction of the artery wall or neointimal thickening. The former, termed remodeling,2 has been successfully addressed to a large extent by the development of endovascular stents: Two landmark clinical trials3,4 established stents as the first mechanical intervention to have a favorable impact on restenosis.Neointimal thickening has been inferred to result most often from vascular smooth muscle cell (VSMC) proliferation.5,6 Indeed, histological inspection of lesions retrieved by directional atherectomy from patients with in-stent restenosis has documented immunohistochemical evidence of markedly augmented SMC proliferation.7 As a result, intense effort has been applied to discern the mechanisms that govern VSMC proliferation after angioplasty and to develop therapies to inhibit VSMC growth. The enthusiasm for this field is reflected by the nearly 900 manuscripts that have been published examining the role of cellular proliferation in restenosis, and, most importantly, by the advent of approaches that have demonstrated significant degrees of clinical success in addressing this aspect of the response to injury.First, intra-arterial brachytherapy achieved success in reducing restenosis after balloon angioplasty for in-stent restenosis.8,9 Second, drug-eluting stents have been developed, employing agents such as the cytostatic/immunomodulatory compound rapamycin and the chemotherapeutic paclitaxel, both of which have been shown to reduce the incidence of restenosis after primary coronary stenting.10–12 In both cases, a strategy targeting proliferating VSMCs at the site of injury has been successful in reducing neointimal lesion formation. The early success of these interventions, however, has exposed a potential liability of an indiscriminate antiproliferative approach for restenosis prevention.The fate of the endothelium in humans after radiation or drug-eluting stent is uncertain at present, but evidence exists to suggest that endothelial recovery may be perturbed. The initial applications of intravascular brachytherapy were complicated by a significant incidence of stent thrombosis occurring up to 9 months after the revascularization procedure,13 Subsequently, the incidence of late thrombosis was shown to be reduced by extending the duration of dual antiplatelet therapy for 6 to 12 months.14 These findings imply that endothelial recovery was inhibited by the antiproliferative approach, which, although intended to prevent VSMC proliferation, also may have inhibited proliferation of endothelial cells (ECs). This possibility is substantiated by studies in animals that reveal protracted deendothelialization in irradiated arteries.15 The apparent inhibition of reendothelialization, manifest as late stent thrombosis, observed after brachytherapy has only been rarely documented after implantation of rapamycin- or paclitaxel-eluting stents,16 but this may be a reflection of the fact that prolonged dual antiplatelet therapy is standard treatment after deployment of these devices. Moreover, recent data have revealed direct inhibition of reendothelialization by paclitaxel17 and inhibition of EC proliferation by rapamycin.18The extent and duration of inhibition of endothelial recovery that result from intravascular radiation or antiproliferative drug–eluting stents, as well as the long-term consequences, remain to be defined at this time; however, the impairment of functional endothelial recovery resulting from these therapies may have undesirable long-term consequences.19In this context, we and others have considered an alternative hypothesis: that stents that develop intimal thickening, as well as a portion of restenosis lesions that originate in nonstented arteries after PTCA, may result, in part, from belated reendothelialization. Previous studies carried out in a variety of animal species have repeatedly shown that extensive endothelial denudation of the artery wall promotes neointimal thickening.20 Because it is difficult to achieve extensive EC denudation without injuring the underlying media, it has been difficult to establish with certainty that the loss of endothelial integrity per se constitutes the sole and/or primary basis for neointimal thickening. Nevertheless, at least 4 studies in the rat model of arterial balloon injury have clearly established an inverse relationship between endothelial integrity and SMC proliferation.Data on the relationship between endothelial integrity and neointimal thickening in human arteries, though limited, are consistent with the results of animal experiments. Davies et al21 harvested coronary arteries from explanted hearts of 6 transplant recipients and found that the severity and extent of EC defects varied directly with the severity and extent of intimal disease. Schwarcz et al22 found foci of—but not complete—reendothelialization in only 6 (38%) of 16 carotid specimens of patients with recurrent carotid artery narrowing after an initially successful endarterectomy. Perhaps most relevant to the proposed investigations, Gravanis and Roubin23 found no EC regeneration among 11 patients dying within 1 month of coronary angioplasty.These studies support the notion that certain functions of the endothelium—including barrier regulation of permeability, thrombogenicity, and leukocyte adherence, as well as production of growth-inhibitory molecules—are critical to prevention of luminal narrowing by neointimal thickening.24 This significance of the antithrombotic function of the endothelium has been highlighted most recently by the finding that selective inhibition of the tissue factor pathway by a gene therapy approach effectively inhibits restenosis.25 The role of the endothelium in excluding leukocyte trafficking has been underscored by studies suggesting significant participation of inflammatory cells in the pathogenesis of neointimal lesions.26Advances in vascular biology and molecular medicine have opened the door to a new era in the prevention of restenosis, providing genetic interventions to modulate the response to injury in the vessel wall. Early investigations into the realm of cardiovascular gene therapy focused on the ability of angiogenic cytokines to accelerate reendothelialization, improve endothelial function, and significantly reduce intimal proliferation in models of balloon-induced arterial injury.27 Capitalizing on the advent of stent technology capable of drug delivery, we have recently shown that gene-eluting stents coated with phVEGF-2 naked plasmid DNA accelerate reendothelialization and inhibit neointimal proliferation in a hypercholesterolemic rabbit iliac angioplasty model.28In the present issue of Circulation, Hedman et al1 report the provocative results of a phase II, randomized, placebo-controlled, double-blind study designed to test the feasibility, tolerability, and efficacy of VEGF gene therapy to prevent restenosis after coronary stenting. Thus, another step toward ameliorating, rather than perturbing, the biology of the artery wall as a restenosis prevention strategy has been taken.The overall restenosis rate in this study was surprisingly low at 6%, virtually precluding the detection of a difference among treatment groups. This might be related to the low-risk profile of the patient population, large reference lumen diameter, and moderate percentage diameter stenoses. Nevertheless, the results establish feasibility and provide safety data about the use of both naked DNA and adenovirus encoding for VEGF. The safety data are especially important in the wake of recent reports suggesting that angiogenic cytokines can accelerate atherogenesis in certain animal models. Celletti et al29 reported increased fatty streak formation and plaque vascularity after VEGF administration in hyperlipidemic animal models. In contrast, the present report by Hedman et al1 adds to a growing literature substantiating the safety and potential efficacy of angiogenic agents, administered as recombinant proteins or as gene therapy, in patients with advanced atherosclerosis (reviewed in Losordo and Kawamoto30). This apparent discrepancy may be explained by the differing role of angiogenesis in nascent atherosclerosis in the animal models versus the established disease in patients. In the animals, the earliest stage of atheroma formation can be influenced by modulating angiogenesis.31 In patients with well-established disease, there is currently no evidence that this is the case.The "endothelial injury/dysfunction" concept and its pathophysiological relationship to atherosclerosis have been propelled by identification of measurable deficiencies in endothelium-dependent functions such as NO production in human atherosclerotic arteries and acceleration of atheroma formation after chemically or mechanically induced endothelial dysfunction. Delinquent reendothelialization has a permissive, if not facilitatory, impact on SMC proliferation,27 a relationship that has been attributed to certain endothelial functions, including barrier regulation of permeability, production of growth-inhibitory molecules, thrombogenicity, and leukocyte adherence, all of which may be critical in the prevention of intimal/neointimal proliferation. This concept has led to the development of new strategies directed to provide endothelial protection in veins used for bypass surgery; to accelerate reendothelialization after balloon-induced arterial injury; and to facilitate endothelialization of prosthetic conduits or endovascular stents.32 The capabilities of certain cytokines to serve as mitogens for ECs in vitro suggest that such molecules might be exploited to accelerate reendothelialization after the injury induced by natural plaque rupture or mechanical endovascular devices. VEGF has the capability of modulating qualitative aspects of EC biology that could be contributory to the maintenance and repair of the endothelium, as evidenced by the finding of the fms-like tyrosine kinase receptor in the mature (quiescent) endothelium of adult organs.33 Consistent with this notion, VEGF directly increases NO release by ECs,34 confirming VEGF's role as a determinant of endothelial maintenance and repair, a feature that is critical for inhibition of SMC proliferation and/or neointimal thickening by the restored endothelium.35As physicians, we are obliged to embrace strategies that offer the highest clinical benefit, while minimizing safety concerns. The rates of restenosis reported with the use of cytostatic and cytotoxic drug-eluting stents are impressive and promise to enhance the outcomes of coronary interventions. However, amid the enthusiasm that has been triggered by the release of these data, we should consider a new therapeutic target—enhanced endothelial recovery. Extensive data suggest that this may be an effective stand-alone strategy for restenosis prevention, serving to inhibit smooth muscle proliferation and perhaps also deter inflammatory cell invasion. The latter phenomenon, although relatively understudied, appears to be a significant component of neointimal lesions,7 which can be inhibited by targeting leukocytes themselves36 or by restoring endothelial barrier function.37An intact endothelium appears to be nature's means of preventing intimal lesion formation. The study by Hedman et al1 unveils a strategy designed to recapitulate nature, rather that thwart it, enhancing endothelial function as a primary strategy for restenosis prevention. As cardiologists, vascular biologists, and physicians, we must now consider an alternative to the "antitumor" approach to restenosis prevention and seek to restore the normal biology of the vessel wall rather than perpetuate its disruption.†Deceased.FootnotesCorrespondence to Douglas W. Losordo, MD, Chief, Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, Boston, MA 02135. E-mail [email protected] References 1 Hedman M, Hartikainen J, Syvänne M, et al. Safety and feasibility of catheter-based local intracoronary VEGF transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the KAT-trial. Circulation. 2003; 107: 2677–2683.LinkGoogle Scholar2 Isner JM. Vascular remodeling: honey, I think I shrunk the artery. Circulation. 1994; 89: 2937–2941.CrossrefMedlineGoogle Scholar3 Bittl JA, Sanborn TA, Tcheng JE, et al. Clinical success, complications and restenosis rates with excimer laser coronary angioplasty. Am J Cardiology. 1992; 70: 1533–1539.CrossrefMedlineGoogle Scholar4 Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent-placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994; 331: 496–501.CrossrefMedlineGoogle Scholar5 Palmaz JC, Hunter G, Carson SN, et al. Postoperative carotid restenosis due to neointimal fibromuscular hyperplasia: clinical, angiographic, and pathological findings. Radiology. 1983; 148: 699–702.CrossrefMedlineGoogle Scholar6 Steele PM, Chesebro JH, Stanson AW, et al. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res. 1985; 57: 105–112.LinkGoogle Scholar7 Kearney M, Pieczek A, Haley L, et al. Histopathology of in-stent restenosis. Circulation. 1997; 95: 1998–2002.CrossrefMedlineGoogle Scholar8 Teirstein PS, Massullo V, Jani S, et al. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation. 2000; 101: 360–365.CrossrefMedlineGoogle Scholar9 Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001; 344: 250–256.CrossrefMedlineGoogle Scholar10 Liistro F, Stankovic G, Di Mario C, 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. 2002; 105: 1883–1886.LinkGoogle Scholar11 Kolodgie FD, John M, Khurana C, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation. 2002; 106: 1195–1198.LinkGoogle Scholar12 Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002; 346: 1773–1780.CrossrefMedlineGoogle Scholar13 Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol. 2000; 36: 65–68.CrossrefMedlineGoogle Scholar14 Waksman R, Ajani AE, White RL, et al. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med. 2002; 346: 1194–1199.CrossrefMedlineGoogle Scholar15 Farb A, Shroff S, John M, et al. Late arterial responses (6 and 12 months) after (32)P beta-emitting stent placement: sustained intimal suppression with incomplete healing. Circulation. 2001; 103: 1912–1919.CrossrefMedlineGoogle Scholar16 Liistro F, Colombo A. Late acute thrombosis after paclitaxel eluting stent implantation. Heart. 2001; 86: 262–264.CrossrefMedlineGoogle Scholar17 Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation. 2001; 104: 473–479.CrossrefMedlineGoogle Scholar18 Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002; 8: 128–135.CrossrefMedlineGoogle Scholar19 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993; 362: 801–805.CrossrefMedlineGoogle Scholar20 Scott-Burden T, Vanhoutte PM. The endothelium as a regulator of vascular smooth muscle proliferation. Circulation. 1993; 87: V-51–V-55.Google Scholar21 Davies MJ, Woolf N, Rrowles PM, et al. Morphology of the endothelium over atherosclerotic plaque in human coronary arteries. Br Heart J. 1988; 60: 459–464.CrossrefMedlineGoogle Scholar22 Schwarcz TH, Yates GN, Ghobrial M, et al. Pathologic characteristic of recurrent carotid artery stenosis. J Vasc Surg. 1987; 5: 280–288.CrossrefMedlineGoogle Scholar23 Gravanis MB, Roubin GS. Histopathologic phenomena at the site of percutaneous transluminal coronary angioplasty: the problem of restenosis. Hum Pathol. 1989; 20: 477–485.CrossrefMedlineGoogle Scholar24 Ross R, Atherosclerosis: a defense mechanism gone awry. Am J Pathol. 1993; 143: 985–1002.Google Scholar25 Zoldhelyi P, Chen ZQ, Shelat HS, et al. Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries. Proc Natl Acad Sci U S A. 2001; 98: 4078–4083.CrossrefMedlineGoogle Scholar26 Welt FG, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol. 2002; 22: 1769–1776.LinkGoogle Scholar27 Asahara T, Chen D, Tsurumi Y, et al. Accelerated restitution of endothelial integrity and endothelium-dependent function following phVEGF165 gene transfer. Circulation. 1996; 94: 3291–3302.CrossrefMedlineGoogle Scholar28 Walter D, Cejna M, Diaz-Sandoval L, et al. Local gene transfer of phVEGF-2 plasmid by gene eluting stents: an alternative strategy for inhibition of restenosis. Circulation. 2002: 106;II-125.Abstract.LinkGoogle Scholar29 Celletti FL, Waugh JM, Amabile PG, et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. 2001; 7: 425–429.CrossrefMedlineGoogle Scholar30 Losordo DW, Kawamoto A. Biological revascularization and the interventional molecular cardiologist: bypass for the next generation. Circulation. 2002; 106: 3002–3005.LinkGoogle Scholar31 Moulton KS, Heller E, Konerding MA, et al. Angiogenesis inhibitors endostatin and TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation. 1999; 99: 1726–1732.CrossrefMedlineGoogle Scholar32 Losordo DW, Isner JM. Vascular endothelial growth factor-induced angiogenesis: crouching tiger or hidden dragon? J Am Coll Cardiol. 2001; 37: 2131–2135.CrossrefMedlineGoogle Scholar33 Peters KG, deVries C, Williams LT. Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. Proc Natl Acad Sci U S A. 1993; 90: 8915–8919.CrossrefMedlineGoogle Scholar34 van der Zee R, Murohara T, Luo Z, et al. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation. 1997; 95: 1030–1037.CrossrefMedlineGoogle Scholar35 Tsurumi Y, Murohara T, Krasinski K, et al. Reciprocal relationship between VEGF and NO in the regulation of endothelial integrity. Nat Med. 1997; 3: 879–886.CrossrefMedlineGoogle Scholar36 Rogers C, Edelman ER, Simon DI. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci U S A. 1998; 95: 10134–10139.CrossrefMedlineGoogle Scholar37 Sata M, Luo Z, Walsh K. Fas ligand overexpression on allograft endothelium inhibits inflammatory cell infiltration and transplant-associated intimal hyperplasia. J Immunol. 2001; 166: 6964–6971.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Lee C, Hsieh M, Roth J, Fu X, Lu C, Hung K, Kuo C and Liu S (2022) Hybrid Core–Shell Nanofibrous Scaffolds/Stents Deliver Angiotensin II Receptor Blocker to Treat Diabetic Artery Disease, ACS Applied Polymer Materials, 10.1021/acsapm.2c00186, 4:6, (4199-4207), Online publication date: 10-Jun-2022. Bae I, Jeong M, Park D, Lim K, Shim J, Kim M and Park J (2020) Mechanical and physio-biological properties of peptide-coated stent for re-endothelialization, Biomaterials Research, 10.1186/s40824-020-0182-x, 24:1, Online publication date: 1-Dec-2020. Liu X (2019) SLC Family Transporters Drug Transporters in Drug Disposition, Effects and Toxicity, 10.1007/978-981-13-7647-4_3, (101-202), . Lee C, Hsieh M, Liu S, Chen J, Liu S, Hsieh I, Wen M and Hung K (2018) Novel bifurcation stents coated with bioabsorbable nanofibers with extended and controlled release of rosuvastatin and paclitaxel, Materials Science and Engineering: C, 10.1016/j.msec.2018.02.027, 88, (61-69), Online publication date: 1-Jul-2018. Meng Z, Gao P, Chen L, Peng J, Huang J, Wu M, Chen K and Zhou Z (2017) Artificial Zinc-Finger Transcription Factor of A20 Suppresses Restenosis in Sprague Dawley Rats after Carotid Injury via the PPARα Pathway, Molecular Therapy - Nucleic Acids, 10.1016/j.omtn.2017.06.010, 8, (123-131), Online publication date: 1-Sep-2017. Ravindranath R, Romaschin A and Thompson M (2016) In vitro and in vivo cell-capture strategies using cardiac stent technology — A review, Clinical Biochemistry, 10.1016/j.clinbiochem.2015.09.012, 49:1-2, (186-191), Online publication date: 1-Jan-2016. Orynbayeva Z, Sensenig R and Polyak B (2015) Metabolic and structural integrity of magnetic nanoparticle-loaded primary endothelial cells for targeted cell therapy, Nanomedicine, 10.2217/nnm.15.14, 10:10, (1555-1568), Online publication date: 1-May-2015. Zohra F, Medved M, Lazareva N and Polyak B (2015) Functional behavior and gene expression of magnetic nanoparticle-loaded primary endothelial cells for targeting vascular stents, Nanomedicine, 10.2217/nnm.15.13, 10:9, (1391-1406), Online publication date: 1-May-2015. Chen J, Li Q, Xu J, Zhang L, Maitz M and Li J (2015) Thromboresistant and rapid-endothelialization effects of dopamine and staphylococcal protein A mediated anti-CD34 coating on 316L stainless steel for cardiovascular devices, Journal of Materials Chemistry B, 10.1039/C4TB01825G, 3:13, (2615-2623) Rosenbaum M, Chaudhuri P, Abelson B, Cross B and Graham L (2015) Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress, Atherosclerosis, 10.1016/j.atherosclerosis.2015.06.018, 241:2, (709-715), Online publication date: 1-Aug-2015. Yuan S, Xiong G, He F, Jiang W, Liang B and Choong C (2015) Multifunctional REDV-conjugated zwitterionic polycarboxybetaine–polycaprolactone hybrid surfaces for enhanced antibacterial activity, anti-thrombogenicity and endothelial cell proliferation, Journal of Materials Chemistry B, 10.1039/C5TB01598G, 3:41, (8088-8101) Lee C, Chang S, Lin Y, Liu S, Wang C, Hsu M, Hung K, Yeh Y, Chen W, Hsieh I and Wen M (2014) Acceleration of re-endothelialization and inhibition of neointimal formation using hybrid biodegradable nanofibrous rosuvastatin-loaded stents, Biomaterials, 10.1016/j.biomaterials.2014.02.017, 35:15, (4417-4427), Online publication date: 1-May-2014. Chen J, Zhou S, Jin J, Tian F, Han Y, Wang J, Liu J and Chen Y (2014) Chronic treatment with trimetazidine after discharge reduces the incidence of restenosis in patients who received coronary stent implantation: A 1-year prospective follow-up study, International Journal of Cardiology, 10.1016/j.ijcard.2014.04.168, 174:3, (634-639), Online publication date: 1-Jul-2014. Li Q, Huang N, Chen J, Xiong K, Chen J, You T and Jin J (2013) An extracellular matrix–like surface modification on titanium improves implant endothelialization through the reduction of platelet adhesion and the capture of endothelial progenitor cells, Journal of Bioactive and Compatible Polymers, 10.1177/0883911512468057, 28:1, (33-49), Online publication date: 1-Jan-2013. Prasad K (2011) Do Statins have a Role in Reduction/Prevention of Post-PCI Restenosis?, Cardiovascular Therapeutics, 10.1111/j.1755-5922.2011.00302.x, 31:1, (12-26), Online publication date: 1-Feb-2013. Chen J, Cao J, Wang J, Maitz M, Guo L, Zhao Y, Li Q, Xiong K and Huang N (2012) Biofunctionalization of titanium with PEG and anti-CD34 for hemocompatibility and stimulated endothelialization, Journal of Colloid and Interface Science, 10.1016/j.jcis.2011.11.039, 368:1, (636-647), Online publication date: 1-Feb-2012. Davis R, Pillai S, Lawrence N and Chellappan S (2012) TNF-α-mediated proliferation of vascular smooth muscle cells involves Raf-1-mediated inactivation of Rb and transcription of E2F1-regulated genes, Cell Cycle, 10.4161/cc.11.1.18473, 11:1, (109-118), Online publication date: 1-Jan-2012. Xu X, Xia J, Yang X, Huang X, Gao D, Zhou J, Lian J and Zhou J (2012) Intermediate-conductance Ca2+-activated potassium and volume-sensitive chloride channels in endothelial progenitor cells from rat bone marrow mononuclear cells, Acta Physiologica, 10.1111/j.1748-1716.2011.02398.x, 205:2, (302-313), Online publication date: 1-Jun-2012. Vedantham K, Chaterji S, Kim S and Park K (2012) Development of a probucol-releasing antithrombogenic drug eluting stent, Journal of Biomedical Materials Research Part B: Applied Biomaterials, 10.1002/jbm.b.32672, 100B:4, (1068-1077), Online publication date: 1-May-2012. Wu X, Zou Y, Zhou Q, Huang L, Gong H, Sun A, Tateno K, Katsube K, Radtke F, Ge J, Minamino T and Komuro I (2011) Role of Jagged1 in Arterial Lesions After Vascular Injury, Arteriosclerosis, Thrombosis, and Vascular Biology, 31:9, (2000-2006), Online publication date: 1-Sep-2011. Zhang X, Chen B, Fu W, Fang Z, Liu Z, Lu W, Shi Z, Chen L and Chen T (2011) The research and preparation of a novel nano biodegradable polymer external reinforcement, Applied Surface Science, 10.1016/j.apsusc.2011.08.030, 258:1, (196-200), Online publication date: 1-Oct-2011. Lin Q, Yan J, Qiu F, Song X, Fu G and Ji J (2010) Heparin/collagen multilayer as a thromboresistant and endothelial favorable coating for intravascular stent, Journal of Biomedical Materials Research Part A, 10.1002/jbm.a.32820, 96A:1, (132-141), Online publication date: 1-Jan-2011. Li Q, Huang N, Chen C, Chen J, Xiong K, Chen J, You T, Jin J and Liang X Oriented immobilization of anti-CD34 antibody on titanium surface for self-endothelialization induction, Journal of Biomedical Materials Research Part A, 10.1002/jbm.a.32812, (n/a-n/a) Garg S, Duckers H and Serruys P (2010) Endothelial progenitor cell capture stents: will this technology find its niche in contemporary practice?, European Heart Journal, 10.1093/eurheartj/ehp591, 31:9, (1032-1035), Online publication date: 1-May-2010. Lee Y, Luo J, Sprague E and Han H (2009) Comparison of Artery Organ Culture and Co-culture Models for Studying Endothelial Cell Migration and Its Effect on Smooth Muscle Cell Proliferation and Migration, Annals of Biomedical Engineering, 10.1007/s10439-009-9877-9, 38:3, (801-812), Online publication date: 1-Mar-2010. Chen J, Chen C, Chen Z, Chen J, Li Q and Huang N (2010) Collagen/heparin coating on titanium surface improves the biocompatibility of titanium applied as a blood-contacting biomaterial, Journal of Biomedical Materials Research Part A, 10.1002/jbm.a.32847, 95A:2, (341-349) Zhao Q, Wei M and Zhao B (2010) Fabrication of stents with endothelial function in vitro , Scandinavian Cardiovascular Journal, 10.3109/14017430903118165, 44:2, (76-81), Online publication date: 1-Jan-2010. Jandt E, Mutschke O, Mahboobi S, Uecker A, Platz R, Berndt A, Böhmer F, Figulla H and Werner G (2010) Stent-based release of a selective PDGF-receptor blocker from the bis-indolylmethanon clas
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