Prevention of venous neointimal hyperplasia by a multitarget receptor tyrosine kinase inhibitor

Sun Hyung Kwon, Li Li, Yuxia He, Jason Chieh Sheng Tey, Huan Li, Ilya Zhuplatov, Seung Jung Kim, Christi M. Terry, Donald K. Blumenthal, Yan Ting Shiu, Alfred K. Cheung

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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-α 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 nM) 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.

Original languageEnglish
Pages (from-to)244-256
Number of pages13
JournalJournal of Vascular Research
Issue number4
StatePublished - 1 Mar 2016

Bibliographical note

Publisher Copyright:
© 2016 S. Karger AG, Basel.


  • Arteriovenous graft
  • Growth factors
  • Neointimal hyperplasia
  • Perfused organ culture
  • Sunitinib


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