title: c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae.
abstract: Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae.
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Skartsis
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Laisel
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Juan Camilo
authors.initials: JC
authors.lastname: Duque
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Marwan
authors.initials: M
authors.lastname: Tabbara
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida;
authors.forename: Omaida C
authors.initials: OC
authors.lastname: Velazquez
authors.affiliation: Division of Nephrology and Hypertension, Albany Medical College, Albany, New York;
authors.forename: Arif
authors.initials: A
authors.lastname: Asif
authors.affiliation: Biomedical Engineering Department, University of Miami, Coral Gables, Florida; and.
authors.forename: Fotios
authors.initials: F
authors.lastname: Andreopoulos
authors.affiliation: Interventional Nephrology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Loay H
authors.initials: LH
authors.lastname: Salman
authors.affiliation: Department of Surgery and Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, Florida; rvazquez@med.miami.edu.
authors.forename: Roberto I
authors.initials: RI
authors.lastname: Vazquez-Padron
mesh_terms: D000368:Aged; D000818:Animals; D001164:Arteriovenous Fistula; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D008875:Middle Aged; D058426:Neointima; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis* / Q000502:physiology; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019009:Proto-Oncogene Proteins c-kit
keywords: arteriovenous fistula; hemodialysis; neointima