Vascular responsiveness of a murine arteriovenous fistula

University of Utah

Understanding the pathobiology of arteriovenous fistula (AVF) maturation failure in hemodialysis patients is requisite to design and implement effective treatments. While intimal hyperplasia and poor lumen expansion contribute to AVF malfunction, compromised vasoreactivity also may play a role. Our murine AVF model consists of the external jugular vein connected to the carotid artery (CA), establishing 3 component parts to the AVF, i.e., proximal CA, venous limb of the AVF (V), and distal CA. First, we tested the hypothesis that endothelium-dependent vasorelaxation is impaired in V’s from 5-month old AVF vs. naïve mice, 3 or 21 -days post-surgery. We reasoned that acute exposure to higher pressures and disturbed flow in the V upon AVF creation would evoke endothelial cell dysfunction. Using isometric tension procedures on V’s from naïve mice, U46619 -evoked vasocontraction was robust, and acetylcholine-stimulated vasorelaxation was 58±12%. However, vasocontraction to U46619, phenylephrine (PE), or potassium chloride (KCL) was absent in V’s at 3 (n=10) or 21-days (n=10) post-surgery, precluding the assessment of vasorelaxation. Next, based on reports that flow velocity is lower and flow patterns are disturbed in the distal vs. proximal CA, we tested the hypothesis that endothelial function is impaired in the distal CA. Surprising to us, maximal acetylcholine-evoked vasorelaxation was greater (p<0.05) in the distal vs. proximal CA, respectively, at 3 (82±10 vs. 55±8%, n=9 each) and 21 (74±14 vs. 56±5%, n=7 each) days, whereas vascular smooth muscle responses to sodium nitroprusside were similar between segments at both time points. Magnetic resonance imaging-based computational fluid dynamic measures indicate blood flow velocity was higher (p<0.05) in the distal (0.99±0.33 m/s; n=3) vs. proximal CA (0.11±0.05 m/s; n=3), and might be responsible for greater endothelial function in this segment. The analysis of flow patterns among AVF components is ongoing. Supported by R01HL153244 NIH/NIDDK (TL, YTS, JDS)