Interplay between skeletal muscle catabolism and remodeling of arteriovenous fistulae via YAP1/TAZ signaling

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Summary Arteriovenous fistula (AVF), an artificially created direct connection between an artery and vein, is the life line for hemodialysis patients suffering from chronic kidney disease (CKD). However, 60-65% of AVFs fail within 1 year of their creation resulting in serious health risks and heavy financial burden to patients. The costs of placing or caring for vascular access exceed $2.8 billion/year. Although, multiple clinical trials have been performed, no viable treatment options have been uncovered. Our long term goal is to identify the cellular and molecular mechanisms of AVF maturation failure so that therapeutic strategies can be developed to prevent and treat AVF failure. Earlier studies demonstrated that CKD-induced neointima (thickening of inner vascular layer) formation and vascular fibrosis are the leading risk factors causing AVF maturation failure. Recently, we found the crosstalk between skeletal muscle catabolism in uremic mice could be related with AVF function failure. Our Preliminary results indicated that myostatin generated in skeletal muscle in uremic mice stimulated the expression of YAP1/TAZ (transcriptional regulators of genes involved in cellular proliferation) which can promote activation of vascular smooth muscle cells (VSMCs) and differentiation of adventitial mesenchymal stem cells (MSCs) into myofibroblasts. These responses result in increased extracellular matrix proteins and progressive vascular fibrosis. The stiffness of extracellular matrix activates YAP1/TAZ which forms a “forward feedback loop”. The result is the enhanced proliferation, migration, and inflammation which lead to AVF maturation failure. We therefore hypothesize that inhibition of myostatin or of YAP1/TAZ will block VSMC activation and MSC differentiation into myofibroblasts resulting in improved AVF functions. Specific Aims proposed in this application will investigate the validity of this hypothesis. In Aim 1 we will examine the effects of myostatin inhibition using a neutralizing peptibody on neointima cells and AVF fibrosis in CKD mice. Aim 2 and 3 will analyze the effects of YAP1 and TAZ knock down on myostatin induced VSMC activation and MSC transdifferentiation in vitro and in vivo, and evaluate if local inhibition of YAP1 activation by FDA-approved drug, Verteporfin suppresses CKD–induced AVF failure in mice. Successful completion of these studies will lead to the development of new therapeutic strategies to prevent and treat AVF failure in dialysis patients.