title: Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Sun Hyung
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: He
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Chieh Sheng
authors.initials: CS
authors.lastname: Tey
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Ilya
authors.initials: I
authors.lastname: Zhuplatov
authors.affiliation: School of Medicine, Division of Nephrology, Ewha Womans University, Seoul, South Korea.
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Christi M
authors.initials: CM
authors.lastname: Terry
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Donald K
authors.initials: DK
authors.lastname: Blumenthal
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Shiu
authors.affiliation: Division of Nephrology & Hypertension, Department of Medicine, University of Utah, Salt Lake City, Utah, U.S.A.|Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, U.S.A.
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D000077214:Becaplermin; D019917:Blood Vessel Prosthesis Implantation / Q000009:adverse effects*; D017536:Carotid Artery, Common / Q000601:surgery; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D006083:Graft Occlusion, Vascular / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006965:Hyperplasia; D007211:Indoles / Q000494:pharmacology*; D007601:Jugular Veins / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D058426:Neointima; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D034421:Sus scrofa; D013997:Time Factors; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D007211:Indoles; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib