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- Title
Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor.
- Authors
Kwon, Sun Hyung; Li, Li; He, Yuxia; Tey, Jason Chieh Sheng; Li, Huan; Zhuplatov, Ilya; Kim, Seung-Jung; Terry, Christi M.; Blumenthal, Donald K.; Shiu, Yan-Ting; Cheung, alfred K.
- Abstract
Background/Aims: Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. Methods: A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. Results: In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-a and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 n M) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 ± 0.25 to 0.04 ± 0.02 (p < 0.05) with treatment. Conclusion: These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions.
- Subjects
HYPERPLASIA; PROTEIN-tyrosine kinases; CELLULAR pathology; DRUG therapy; CELL cycle
- Publication
Journal of Vascular Research, 2016, Vol 52, Issue 4, p244
- ISSN
1018-1172
- Publication type
Article
- DOI
10.1159/000442977