NDT Advance Access originally published online on June 30, 2007
Nephrology Dialysis Transplantation 2007 22(11):3139-3146; doi:10.1093/ndt/gfm415
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Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model*
1Department of Medicine and 2Departments of Pharmacology & Toxicology and Biochemistry, 3Veterans Affairs Salt Lake City Healthcare System, University of Utah, Salt Lake City, Utah, USA and 4Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
Correspondence and offprint requests to: Alfred K. Cheung, MD, Dialysis Program, 85 North Medical Drive East, University of Utah, Salt Lake City, UT 84112, USA. Email: alfred.cheung{at}hsc.utah.edu
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Abstract |
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Background. Implantation of a haemodialysis arteriovenous graft is often followed by the development of neointimal hyperplasia (NH) at the venous anastomosis. The nature of the proliferating cells in these lesions is not well understood. A better understanding of the cells contributing to NH is important to the development of preventive strategies.
Methods. Carotid-jugular PTFE grafts were placed in 21 pigs and characterized at various time points following implantation. Venous anastomotic tissues were harvested at 1, 7, 14, 21, 28 or 49 post-operative days for histology and immunohistochemistry.
Results. Van Gieson staining of the tissues showed that NH was apparent as early as day 7 and progressed over time. Even by day 1, there were cells expressing the proliferation marker Ki-67 in the venous adventitia, but not the media, at the anastomosis. Double immunohistochemical staining showed that these cells were positive for 
-smooth muscle actin (-SMA), but negative for smooth muscle myosin heavy chain (SM MHC), suggesting that the proliferating cells were myofibroblasts rather than smooth muscle cells. By day 7, proliferating cells were abundant in the adventitia and began to appear in the media, surrounded by extracellular matrix visualized using Trichrome staining. By day 49, -SMA-positive, SM MHC-negative cells were predominant in the NH, and Ki-67 staining had largely vanished.
Conclusions. These results are consistent with the hypothesis that adventitial fibroblasts are transformed into myofibroblasts and begin to proliferate within hours after graft placement. Migration of these cells towards the vessel lumen with subsequent proliferation appears to be a major contributor to NH formation. The pivotal role of the adventitial fibroblasts in the pathogenesis of NH provides a compelling rationale for therapies that target the transformation, proliferation and migration of these cells to prevent arteriovenous graft stenosis.
Keywords: adventitial fibroblast; haemodialysis; immunohistochemistry; Ki-67; myofibroblast; neointimal hyperplasia; smooth muscle cell, -smooth muscle actin; smooth muscle myosin heavy chain; vascular access; vein
*This work was previously presented in free communication form at the American Society of Nephrology Annual Meeting, in San Diego, California on November 18, 2006.
Received for publication: 16. 1.07
Accepted in revised form: 4. 6.07
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