Abstract 667: Endothelial Glucocorticoid Receptor Deficiency Affects Arteriovenous Fistula Maturation

Abstract

Objectives: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access in patients with end-stage chronic kidney disease (CKD); however, AVF have high rates of failure due to aggressive neointimal hyperplasia (NIH) caused by vascular inflammation and endothelial-to-mesenchymal transition (EndMT). Since the endothelial glucocorticoid receptor is a negative regulator of vascular inflammation, we hypothesized that inhibition of the endothelial glucocorticoid receptor would promote EndMT and accelerate NIH. Methods: Aortocaval AVF were created in GR fl/fl , Tie-1 Cre + (GR EC-KO ) mice and control mice GR fl/fl , Tie-1 Cre - ( GR fl/fl ). Three weeks prior to AVF, CKD was created via 5/6 nephrectomy (Nx); ultrasound was used to determine AVF diameter and patency at postoperative days 7, 14, and 21. AVF were harvested at days 3, 7 and 21 and examined with histology, immunofluorescence, and Western blot. Results: At postoperative day 21, AVF diameter was significantly decreased in GR EC-KO mice, whereas there was increased AVF wall thickness and accumulation of extracellular matrix (ECM) components fibronectin (p<0.005), collagen1 (p<0.005), collagen3 (p<0.005), as well as p-smad2 (p<0.001), compared to the control mice. Endothelial cells in the AVF of GR EC-KO mice had significantly increased immunoreactivity of the mesenchymal markers notch3 (p<0.0001), vimentin (p<0.0001) and FSP-1 (p<0.005) compared to control mice, consistent with increased EndMT. There was no difference between GR EC-KO and control mice treated with 5/6Nx regarding body weight or aortic diameter. Conclusion: Absence of the endothelial glucocorticoid receptor promotes EndMT and wall thickening during venous remodeling in the CKD environment. These data suggest that the endothelial glucocorticoid receptor serves as a physiologic regulator of venous remodeling during AVF maturation.