Abstract 15608: Deficiency of Tlr4 Homologue Rp105 Aggravates Outward Remodelling in a Murine Model of Arteriovenous Fistula Failure
Introduction: Arteriovenous access dysfunction is still the Achilles’ heel of hemodialysis in patients with end-stage renal disease (ESRD) with a 1-year primary patency of only 60%.The pathophysiology of arteriovenous fistula (AVF) maturation failure is unknown but impaired outward remodeling and intimal hyperplasia are both considered to contribute. Radio protective (RP)105 is an important regulator of inflammatory TLR4 signalling, expressed on numerous cell types. In the present study, we defined cell specific effects of RP105-/- on vascular smooth muscle cells (VSMCs) and macrophages (mφ) in vitro and in vivo effects of RP105-/- on AVF maturation in a murine model of AVF failure.
Methods: All in vitro experiments were performed on primary cells isolated from RP105-/- and wild type (WT) mice. AVFs were created in an end-to-side manner between v.jugularis and carotid a. in RP105-/- (n=13) and WT (n=11) mice. AVFs were harvested at day 14 and processed for morphometric analysis and immunohistochemistry. MMPSense probe was used to measure in vivo MMPs activity.
Results: In vitro, anti-inflammatory (M2) mφ of RP105-/-mice showed increased IL10 (ELISA) compared to WT. Venous VSMCs from WT mice exhibited increased mRNA of RP105 and TLR4 compared to arterial VSMCs, whereas proliferation rate of venous VSMCs was 50% lower in RP105-/- cells. In vivo, a shift towards M2 mφ and a 70% reduction in CD3+ T cells was observed in RP105-/- mice (fig.1a,b). MMP-activity was reduced by 50% in RP105-/- (fig.1c). Amount of SMA/Ki67++ VSMCs was decreased by 31%. Overall, RP105-/- mice showed 26% smaller circumference of the external jugular vein (fig.1d).
Conclusions: Deletion of RP105 results in a marked decrease in venous outward remodeling in AVF. The latter might relate to a shift towards M2 mφ, reduction in MMP activity and decreased VSMCs proliferation in the venous outflow tract of AVF, illustrating the complex interactions between inflammation and VSMC biology in AVF maturation.
Author Disclosures: T. Bezhaeva: None. C. Wong: None. M. de Vries: None. E. van der Veer: None. C. van Alem: None. J. Rotmans: None. P. Quax: None.
- © 2016 by American Heart Association, Inc.