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

Abstract

Abstract 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, β-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 β-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 (αSMA), loss of cell–cell adhesions, and the expression of the myofibroblast marker, integrin subunit β6 (ITGB6), indicated transition to myofibroblasts in mouse AVF. Nuclear translocation of β-catenin, decreased axin2, and increased c-myc expression were also observed in the AVF, indicating activated β-catenin signaling. To confirm that β-catenin signaling contributes to AVF lesions, β-catenin signaling was inhibited with pyrvinium pamoate; β-catenin inhibition significantly attenuated AVF thickening and decreased myofibroblasts. In HUVECs, barometric pressure-induced nuclear localization of β-catenin and increased expression of the myofibroblast markers, αSMA and ITGB6. These changes were attenuated via pretreatment with β-catenin inhibition. Conclusions The results of this study indicate that mechanical disturbance in AVF activates β-catenin signaling to induce the transition of endothelial cells to myofibroblasts. This signaling cascade can be targeted to maintain AVF patency.

Keywords

• Arteriovenous fistula (AVF)
• β-catenin
• Hemodialysis
• Myofibroblast