Adventitial endothelial implants reduce matrix metalloproteinase-2 expression and increase luminal diameter in porcine arteriovenous grafts

ObjectiveVascular access dysfunction is a major problem in hemodialysis patients. Only 50% of arteriovenous grafts (AVGs) will remain patent 1 year after surgery. AVGs frequently develop stenoses and occlusions at the venous anastomoses in the venous outflow tract. Lumen diameter is not only determined by intimal thickening but is also influenced by remodeling of the vessel wall. Vascular remodeling requires degradation and reorganization of the extracellular matrix by the degradation enzymes, matrix metalloproteinases (MMPs). In this study, we aimed to provide further insight into the mechanism of endothelial regulation of vascular remodeling and luminal narrowing in AVGs.MethodsEnd-to-side carotid artery–jugular vein polytetrafluoroethylene grafts were created in 20 domestic swine. The anastomoses and outflow vein were treated with Gelfoam matrices (Pfizer, New York, NY) containing allogeneic porcine aortic endothelial (PAE, n = 10) cells or control matrices without cells (n = 10), and the biologic responses to PAE implants were investigated 3 and 28 days postoperatively. Angiograms before euthanasia were compared with baseline angiograms. Tissue sections were stained with hematoxylin and eosin, Verhoeff elastin, and antibodies specific to MMP-9 and MMP-2 and underwent histopathologic, morphometric and immunohistochemical analysis.ResultsVeins treated with PAE cell implants had a 2.8-fold increase in venous lumen diameter compared with baseline (P < .05), a 2.3-fold increase in lumen diameter compared with control, and an 81% decrease in stenosis (P < .05) compared with control at 28 days. The increase in lumen diameter by angiographic analysis correlated with morphometric analysis of tissue sections. PAE implants increased the venous lumen area 2.3-fold (P < .05), decreased venous luminal occlusion 66%, and increased positive venous remodeling 1.9-fold (P < .05) compared with control at 28 days. PAE cell implants reduced MMP-2 expression and neovascularization at 3 and 28 days and adventitial fibrosis at 28 days, suggesting a role of the implants in controlling the affects of medial and adventitial cells in the response to vascular injury.ConclusionsThese results demonstrate that the adventitial application of endothelial implants significantly reduced MMP-2 expression within the venous wall, and increased venous lumen diameter and positive remodeling in a porcine arteriovenous graft model. Adventitial endothelial implants may be useful in decreasing luminal narrowing in a clinical setting.Clinical RelevanceVascular access dysfunction is the leading cause of hospitalization and morbidity in patients receiving hemodialysis for end-stage renal disease. Data indicate that most arteriovenous grafts fail due to the formation of stenosis at the vein-graft anastomotic and venous outflow sites. The stenoses result in luminal narrowing and subsequent graft thrombosis and failure. A satisfactory long-term pharmacologic means of preventing stenosis due to intimal hyperplasia and negative remodeling in hemodialysis grafts has yet to be found. In a large animal model of arteriovenous grafts, we show that placement of an adventitial endothelial implant significantly increased venous lumen diameter at 28 days