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      Comparison of reendothelialization and neointimal formation with stents coated with antibodies against endoglin and CD34 in a porcine model

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          Abstract

          Anti-CD34 coated stents are the only commercialized antibody-coated stents currently used for coronary artery diseases with various limitations. Endoglin plays important roles in the proliferation of endothelial cells and vascular remodeling and could be an ideal target surface molecule. The objective of this study was to investigate the efficacy of stents coated with anti-endoglin antibodies (ENDs) in terms of endothelial recovery and the reduction of neointimal formation. The performance of ENDs was evaluated by comparing with stents coated with anti-CD34 antibodies (CD34s), sirolimus-eluting stents (SESs), and bare metal stents (BMSs). Stents were randomly assigned and placed in the coronary arteries of juvenile pigs. Histomorphometric analysis and scanning electron microscopy were performed after stent implantation. Our results showed at 14 days after stent implantation, the neointima area and percent area stenosis in ENDs and CD34s were remarkably decreased compared with those in BMSs and SESs ( P<0.05). Moreover, the percentage of reendothelialization was significantly higher in ENDs and CD34s than that in SESs or BMSs at both 7 and 14 days ( P<0.05). There was no difference in the neointima area, percent area stenosis, and percentage of reendothelialization in ENDs compared with CD34s. The artery injury and the inflammation scores were similar in all groups at both 7 and 14 days. Our results demonstrate that the performance of ENDs is similar to the commercial CD34s, without the disadvantages of CD34s, and both are better than SESs and BMSs. ENDs potentially offer an alternative approach to reduce restenotic process and enhance reendothelialization after stent implantation.

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          Most cited references 37

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          A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.

          The need for repeated treatment of restenosis of a treated vessel remains the main limitation of percutaneous coronary revascularization. Because sirolimus (rapamycin) inhibits the proliferation of lymphocytes and smooth-muscle cells, we compared a sirolimus-eluting stent with a standard uncoated stent in patients with angina pectoris. We performed a randomized, double-blind trial to compare the two types of stents for revascularization of single, primary lesions in native coronary arteries. The trial included 238 patients at 19 medical centers. The primary end point was in-stent late luminal loss (the difference between the minimal luminal diameter immediately after the procedure and the diameter at six months). Secondary end points included the percentage of in-stent stenosis of the luminal diameter and the rate of restenosis (luminal narrowing of 50 percent or more). We also analyzed a composite clinical end point consisting of death, myocardial infarction, and percutaneous or surgical revascularization at 1, 6, and 12 months. At six months, the degree of neointimal proliferation, manifested as the mean (+/-SD) late luminal loss, was significantly lower in the sirolimus-stent group (-0.01+/-0.33 mm) than in the standard-stent group (0.80+/-0.53 mm, P<0.001). None of the patients in the sirolimus-stent group, as compared with 26.6 percent of those in the standard-stent group, had restenosis of 50 percent or more of the luminal diameter (P<0.001). There were no episodes of stent thrombosis. During a follow-up period of up to one year, the overall rate of major cardiac events was 5.8 percent in the sirolimus-stent group and 28.8 percent in the standard-stent group (P<0.001). The difference was due entirely to a higher rate of revascularization of the target vessel in the standard-stent group. As compared with a standard coronary stent, a sirolimus-eluting stent shows considerable promise for the prevention of neointimal proliferation, restenosis, and associated clinical events.
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            Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.

            Emerging data suggest that a subset of circulating human CD34(+) cells have phenotypic features of endothelial cells. Whether these cells are sloughed mature endothelial cells or functional circulating endothelial precursors (CEPs) is not known. Using monoclonal antibodies (MoAbs) to the extracellular domain of the human vascular endothelial receptor-2 (VEGFR-2), we have shown that 1.2 +/- 0.3% of CD34(+) cells isolated from fetal liver (FL), 2 +/- 0.5% from mobilized peripheral blood, and 1.4 +/- 0.5% from cord blood were VEGFR-2(+). In addition, most CD34(+)VEGFR-2(+) cells express hematopoietic stem cell marker AC133. Because mature endothelial cells do not express AC133, coexpression of VEGFR-2 and AC133 on CD34(+) cells phenotypically identifies a unique population of CEPs. CD34(+)VEGFR-2(+) cells express endothelial-specific markers, including VE-cadherin and E-selectin. Also, virtually all CD34(+)VEGFR-2(+) cells express the chemokine receptor CXCR4 and migrate in response to stromal-derived factor (SDF)-1 or VEGF. To quantitate the plating efficiency of CD34(+) cells that give rise to endothelial colonies, CD34(+) cells derived from FL were incubated with VEGF and fibroblast growth factor (FGF)-2. Subsequent isolation and plating of nonadherent FL-derived VEGFR-2(+) cells with VEGF and FGF-2 resulted in differentiation of AC133(+ )VEGFR-2(+) cells into adherent AC133(-)VEGFR-2(+)Ac-LDL(+ )(acetylated low-density lipoprotein) colonies (plating efficiency of 3%). In an in vivo human model, we have found that the neo-intima formed on the surface of left ventricular assist devices is colonized with AC133(+)VEGFR-2(+) cells. These data suggest that circulating CD34(+) cells expressing VEGFR-2 and AC133 constitute a phenotypically and functionally distinct population of circulating endothelial cells that may play a role in neo-angiogenesis.
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              Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model.

              Restenosis is a reparative response to arterial injury occurring with percutaneous coronary revascularization. However, the quantitative characteristics of the relation between vessel injury and the magnitude of restenotic response remain unknown. This study was thus performed to determine the relation between severity of vessel wall injury and the thickness of resulting neointimal proliferation in a porcine model of coronary restenosis. Twenty-six porcine coronary artery segments in 24 pigs were subjected to deep arterial injury with use of overexpanded, percutaneously delivered tantalum wire coils. The vessels were studied microscopically 4 weeks after coil implantation to measure the relation between the extent of injury and the resulting neointimal thickness. For each wire site, a histopathologic score proportional to injury depth and the neointimal thicknesses at that site were determined. Mean injury scores were compared with both mean neointimal thickness and planimetry-derived area percent lumen stenosis. The severity of vessel injury strongly correlated with neointimal thickness and percent diameter stenosis (p less than 0.001). Neointimal proliferation resulting from a given wire was related to injury severity in adjacent wires, suggesting an interaction among effects at injured sites. If the results in this model apply to human coronary arteries, restenosis may depend on the degree of vessel injury sustained during angioplasty.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                17 April 2015
                : 9
                : 2249-2256
                Affiliations
                [1 ]The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Department of Cardiology, Anzhen Hospital Affiliated to Capital Medical University, Beijing, People’s Republic of China
                [2 ]Department of Cardiology, Huimin People’s Hospital, Binzhou, People’s Republic of China
                [3 ]Department of Cardiology, Binzhou Central Hospital, Binzhou, People’s Republic of China
                [4 ]School of Medicine, University of California, San Diego, CA, USA
                [5 ]Tianjin SunnyPeak Biotech Co, Ltd, Tianjin, People’s Republic of China
                Author notes
                Correspondence: Xian-Tao Song, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Department of Cardiology, Anzhen Hospital Affiliated to Capital Medical University, No. 2, Anzhen Road, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +86 10 64456981, Fax +86 10 64453756, Email songxiantao@ 123456medmail.com.cn
                Li-Jun Meng, Department of Cardiology, Binzhou Central Hospital, Binzhou 251700, People’s Republic of China, Tel +86 543 5325877, Fax +86 543 5322880, Email zxyymlj@ 123456126.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-9-2249
                10.2147/DDDT.S81257
                4408966
                © 2015 Cui et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                endothelialization, restenosis, anti-cd34

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