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      Perivascular Endothelial Implants Inhibit Intimal Hyperplasia in a Model of Arteriovenous Fistulae: A Safety and Efficacy Study in the Pig

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          Abstract

          Vascular access complications are a major problem in hemodialysis patients. Native arteriovenous fistulae, historically the preferred mode of access, have a patency rate of only 60% at 1 year. The most common mode of failure is due to progressive stenosis at the anastomotic site. We have previously demonstrated that perivascular endothelial cell implants inhibit intimal thickening following acute balloon injury in pigs and now seek to determine if these implants provide a similar benefit in the chronic and more complex injury model of arteriovenous anastomoses. Side-to-side femoral artery-femoral vein anastomoses were created in 24 domestic swine and the toxicological, biological and immunological responses to allogeneic endothelial cell implants were investigated 3 days and 1 and 2 months postoperatively. The anastomoses were wrapped with polymer matrices containing confluent porcine aortic endothelial cells (PAE; n = 14) or control matrices without cells (n = 10). PAE implants significantly reduced intimal hyperplasia at the anastomotic sites compared to controls by 68% (p <0.05) at 2 months. The beneficial effects of the PAE implants were not due to differences in the rates of reendothelialization between the groups. No significant immunological response to the allogeneic endothelial cells that impacted on efficacy was detected in any of the pigs. No apparent toxicity was observed in any of the animals treated with endothelial implants. These data suggest that perivascular endothelial cell implants are safe and reduce early intimal hyperplasia in a porcine model of arteriovenous anastomoses.

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          Most cited references 2

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          Cultured endothelial cells produce heparinlike inhibitor of smooth muscle cell growth

          Using cultured cells from bovine and rat aortas, we have examined the possibility that endothelial cells might regulate the growth of vascular smooth muscle cells. Conditioned medium from confluent bovine aortic endothelial cells inhibited the proliferation of growth-arrested smooth muscle cells. Conditioned medium from exponential endothelial cells, and from exponential or confluent smooth muscle cells and fibroblasts, did not inhibit smooth muscle cell growth. Conditioned medium from confluent endothelial cells did not inhibit the growth of endothelial cells or fibroblasts. In addition to the apparent specificity of both the producer and target cell, the inhibitory activity was heat stable and not affected by proteases. It was sensitive flavobacterium heparinase but not to hyaluronidase or chondroitin sulfate ABC lyase. It thus appears to be a heparinlike substance. Two other lines of evidence support this conclusion. First, a crude isolate of glycosaminoglycans (TCA-soluble, ethanol-precipitable material) from endothelial cell-conditioned medium reconstituted in 20 percent serum inhibited smooth muscle cell growth; glycosaminoglycans isolated from unconditioned medium (i.e., 0.4 percent serum) had no effect on smooth muscle cell growth. No inhibition was seen if the glycosaminoglycan preparation was treated with heparinase. Second, exogenous heparin, heparin sulfate, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate ABC, and hyaluronic acid were added to 20 percent serum and tested for their ability to inhibit smooth muscle cell growth. Heparin inhibited growth at concentrations as low as 10 ng/ml. Other glycosaminoglycans had no effect at doses up to 10 μg/ml. Anticoagulant and non- anticoagulant heparin were equally effective at inhibiting smooth muscle cell growth, as they were in vivo following endothelial injury (Clowes and Karnovsk. Nature (Lond.). 265:625-626, 1977; Guyton et al. Circ. Res. 46:625-634, 1980), and in vitro following exposure of smooth muscle cells to platelet extract (Hoover et al. Circ. Res. 47:578-583, 1980). We suggest that vascular endothelial cells may secrete a heparinlike substance in vivo which may regulate the growth of underlying smooth muscle cells.
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            Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia.

            Perlecan, a heparan sulfate proteoglycan, has been suggested to be critical for regulation of vascular repair. We generated clones of endothelial cells expressing an antisense vector targeting domain III of perlecan. Transfected cells produced significantly less perlecan than parent cells and showed a reduced ability to inhibit the binding and mitogenic activity of fibroblast growth factor-2 in vascular smooth muscle cells. Endothelial cells were seeded onto three-dimensional polymeric matrices and implanted adjacent to porcine carotid arteries subjected to deep injury. Although the parent endothelial cells prevented occlusive thrombosis, perlecan-deficient cells were completely ineffective. The ability of endothelial cells to inhibit intimal hyperplasia, however, was abrogated only in part by perlecan suppression. The differential regulation by perlecan of these different aspects of vascular repair may explain why control of clinical clot formation does not lead to full control of intimal hyperplasia. Thus the use of genetically modified tissue-engineered cells provides a new approach for dissecting the role of specific factors within the complex environment of the blood vessel wall.
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              Author and article information

              Journal
              JVR
              J Vasc Res
              10.1159/issn.1018-1172
              Journal of Vascular Research
              S. Karger AG
              1018-1172
              1423-0135
              2002
              December 2002
              17 January 2003
              : 39
              : 6
              : 524-533
              Affiliations
              aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass., bDepartment of Medicine, Massachusetts General Hospital, Boston, Mass., cPharmacology and Surgery, Charles River Laboratories, Worcester, Mass., dDepartment of Surgery, Washington University of Medicine, St. Louis, Mo., eCardiovascular Division, Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, Mass., USA
              Article
              67207 J Vasc Res 2002;39:524–533
              10.1159/000067207
              12566978
              © 2002 S. Karger AG, Basel

              Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

              Page count
              Figures: 5, Tables: 2, References: 27, Pages: 10
              Categories
              Research Paper

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