title: Vascular remodeling and intimal hyperplasia in a novel murine model of arteriovenous fistula failure.
abstract: OBJECTIVE
  The arteriovenous fistula (AVF) still suffers from a high number of failures caused by insufficient outward remodeling and intimal hyperplasia (IH) formation from which the exact mechanism is largely unknown. A suitable animal model is of vital importance in the unraveling of the underlying pathophysiology. However, current murine models of AVF failure do not incorporate the surgical configuration that is commonly used in humans. Because the hemodynamic profile is one of the key determinants that play a role in vascular remodeling in the AVF, it is preferable to use this same configuration in an animal model. Here we describe a novel murine model of AVF failure in which the configuration (end-to-side) is similar to what is most frequently performed in humans.
  
  
  METHODS
  An AVF was created in 45 C57BL/6 mice by anastomosing the end of a branch of the external jugular vein to the side of the common carotid artery with interrupted sutures. The AVFs were harvested and analyzed histologically at days 7, 14, and 28. Identical veins of unoperated-on mice served as controls. Intravenous near-infrared fluorescent fluorophores were used to assess the patency of the fistula.
  
  
  RESULTS
  The patency rates at days 7, 14, and 28 days were 88%, 90%, and 50%, respectively. The mean circumference increased up to day 14, with a maximum 1.4-fold increase at day 7 compared with the control group (1.82 ± 0.7 vs 1.33 ± 0.3 mm; P = .443). Between days 14 and 28, the circumference remained constant (2.36 ± 0.2 vs 2.45 ± 0.2 mm; P = .996). At 7 days after surgery, the intimal area consisted mainly of an acellular layer that was structurally analogous to a focal adherent thrombus. Starting at 14 days after surgery, venous IH increased significantly compared with the unoperated-on group (14 days: 115,090 ± 22,594 μm(2), 28 days: 234,619 ± 47,828 μm(2), unoperated group: 2368 ± 1056 μm(2); P = .001 and P < .001, respectively) and was mainly composed of cells positive for α-smooth muscle actin. We observed leukocytes in the adventitial side of the vein at all time points.
  
  
  CONCLUSIONS
  Our novel murine AVF model, which incorporates a clinically relevant configuration of the anastomosis, displays similar features that are characteristic of failing human AVFs. Moreover, our findings suggest that coagulation and inflammation could both potentially play an important role in the formation of IH and subsequent AVF failure. Near-infrared fluoroscopy was a suitable alternative for conventional imaging techniques. This murine AVF-model is a valuable addition to the AVF animal model arsenal.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Wong
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.affiliation: Division of Nephrology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joost R
authors.initials: JR
authors.lastname: van der Vorst
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Vahrmeijer
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anton Jan
authors.initials: AJ
authors.lastname: van Zonneveld
authors.affiliation: Division of Nephrology, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Prabir
authors.initials: P
authors.lastname: Roy-Chaudhury
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: j.i.rotmans@lumc.nl.
authors.forename: Joris I
authors.initials: JI
authors.lastname: Rotmans
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D017536:Carotid Artery, Common / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D003094:Collagen / Q000378:metabolism; D006439:Hemodynamics; D006965:Hyperplasia; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007601:Jugular Veins / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D058426:Neointima; D013536:Suture Techniques / Q000009:adverse effects; D013997:Time Factors; D017211:Treatment Failure; D014654:Vascular Patency; D020246:Venous Thrombosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D003094:Collagen