Pharmacological approach for inhibition of neointimal hyperplasia associated with arteriovenous hemodialysis graft stenosis

Venous neointimal hyperplasia (NH) leading to stenosis, thrombosis, annd failure of hemodialysis ateriovenous grafts (AVG) is an important problem that has no effective treatment for prevention. Many factors contribute to venous NH development, however, the underlying mechanisms are incompletely understood. The objectives are: i) to evaluate the of sunitinib on suppressing NH-promoting events in vivo, and on attenuating venous NH formation in an ex vivo perfused culture system; ii) to investigate the genomic responses underlying the pathophysiology of venous NH in a porcine AVG stenosis model; iii) to assess the genomic responses of porcine venous endothelial cells exposed to physiological or pathophysiological hemodynaic shear stress. In a porcine AVG model, evaluated expression of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and their cognate receptors was seen at the venous anastomosis within 2 weeks after AVG placement. Sunitinib exhibited antiproliferative and antimigratory properties against vasular smooth muscle cells and endothelial cells (EC), which was supported by changes in the phosphorylation state of expression of the signaling proteins involved. Sunitinib also significantly attenuated the formation of venous NH in vein segments exposed to nonphysiologogical flow in an ex vivo culture model. We investigated the genomic changes underlying the NH-prone and NH-resistant vein regions in a porcine AVG stenosis model to identify potential therapeutic targets to inhibit NH. Using microarray, gene expression changes in these two distinct regions ere examined 5 and 14 days following graft placement. In the NH-prone region, genes related to regulation of cell proliferation were most enriched among thep significantly up-regulated genes at day 5, while up-regulated genes associated with osteo/chondrogenic vascular remodeling were most enriched at day 14. At both time periods, genes related to muscle phenotype were significantly down-regulated. Lastly, shear stress-responsive genes in porcine venous ECs exposed to physiologically low or pathologically high shear stress for a prolonged period were studied. We found that shear stress can induce a variety of cellular processes in ECs which may contribute to venous NH development. Our findings demonstrate the utility of an ex vivo perfused vein model to investigate NH-preventive pharmacotherapies , such as sunitinib. Our gene expression studies also provide insight into improved understanding of the molecular mechanisms that may be implicated in the development of venous NH.