Inhibition of beta-catenin signaling attenuates arteriovenous fistula thickening in mice by suppressing myofibroblasts

Background: Arteriovenous fistula (AVF) is the most important vascular access for hemodialysis; however, preventive treatment to maintain the patency of AVFs has not been developed. In endothelium, beta-catenin functions in both the intercellular adherens complex and signaling pathways that induce the transition of endothelial cells to myofibroblasts in response to mechanical stimuli. We hypothesize that mechanical disturbances in the AVF activate beta-catenin signaling leading to the transition of endothelial cells to myofibroblasts, which cause AVF thickening. The present study aimed to test this hypothesis. Methods: Chronic kidney disease in mice was induced by a 0.2% adenine diet. AVFs were created by aortocaval puncture. Human umbilical vein endothelial cells (HUVECs) were used in the cell experiments. A pressure-culture system was used to simulate mechanical disturbances of the AVF. Results: Co-expression of CD31 and smooth muscle alpha-actin (alpha SMA), loss of cell-cell adhesions, and the expression of the myofibroblast marker, integrin subunit beta 6 (ITGB6), indicated transition to myofibroblasts in mouse AVF. Nuclear translocation of beta-catenin, decreased axin2, and increased c-myc expression were also observed in the AVF, indicating activated beta-catenin signaling. To confirm that beta-catenin signaling contributes to AVF lesions, beta-catenin signaling was inhibited with pyrvinium pamoate; beta-catenin inhibition significantly attenuated AVF thickening and decreased myofibroblasts. In HUVECs, barometric pressure-induced nuclear localization of beta-catenin and increased expression of the myofibroblast markers, alpha SMA and ITGB6. These changes were attenuated via pretreatment with beta-catenin inhibition. Conclusions: The results of this study indicate that mechanical disturbance in AVF activates beta-catenin signaling to induce the transition of endothelial cells to myofibroblasts. This signaling cascade can be targeted to maintain AVF patency.