title: Disturbed shear stress reduces Klf2 expression in arterial-venous fistulae in vivo.
abstract: Laminar shear stress (SS) induces an antiproliferative and anti-inflammatory endothelial phenotype and increases Klf2 expression. We altered the diameter of an arteriovenous fistula (AVF) in the mouse model to determine whether increased fistula diameter produces disturbed SS in vivo and if acutely increased disturbed SS results in decreased Klf2 expression. The mouse aortocaval fistula model was performed with 22, 25, or 28 gauge needles to puncture the aorta and the inferior vena cava. Duplex ultrasound was used to examine the AVF and its arterial inflow and venous outflow, and SS was calculated. Arterial samples were examined with western blot, immunohistochemistry, and immunofluorescence analysis for proteins and qPCR for RNA. Mice with larger diameter fistulae had diminished survival but increased AVF patency. Increased SS magnitudes and range of frequencies were directly proportional to the needle diameter in the arterial limb proximal to the fistula but not in the venous limb distal to the fistula, with 22-gauge needles producing the most disturbed SS in vivo. Klf2 mRNA and protein expression was diminished in the artery proximal to the fistula in proportion to increasing SS. Increased fistula diameter produces increased SS magnitude and frequency, consistent with disturbed SS in vivo. Disturbed SS is associated with decreased mRNA and protein expression of Klf2. Disturbed SS and reduced Klf2 expression near the fistula are potential therapeutic targets to improve AVF maturation.
authors.affiliation: Veterans Affairs Connecticut Healthcare Systems, West Haven, Connecticut Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Protack
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Go
authors.initials: G
authors.lastname: Kuwahara
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Pathology, Yale University School of Medicine, New Haven, Connecticut Division of Cancer Biology,  National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hall
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Roland
authors.initials: R
authors.lastname: Assi
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Kirstyn E
authors.initials: KE
authors.lastname: Brownson
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Foster
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Hualong
authors.initials: H
authors.lastname: Bai
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Mo
authors.initials: M
authors.lastname: Wang
authors.affiliation: Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
authors.affiliation: Veterans Affairs Connecticut Healthcare Systems, West Haven, Connecticut Vascular Biology & Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut Department of Surgery, Yale University School of Medicine, New Haven, Connecticut alan.dardik@yale.edu.
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
keywords: Arteriovenous fistula; disturbed flow; kruppel‐like factor 2; laminar flow; shear stress