BCCMA: Cardiovascular Remodeling following Arteriovenous Fistula Creation: Autophagy Contributes to Adverse Arteriovenous Fistula Remodeling

Project Summary/Abstract The arteriovenous fistula (AVF) is the lifeline for Veterans with end-stage kidney disease (ESKD) requiring hemodialysis therapy. Arteriovenous fistulas (AVF) are the preferred vascular access for hemodialysis patients with end stage kidney disease. A large proportion of AVFs (30-60%) created in the United States fail to successfully mature. The high failure rates after AVF creation reflect our poor understanding of the mechanisms leading to AVF maturation failure; and the lack of therapies to prevent or treat this problem represents an unmet clinical need. Our Collaborative Merit Award (CMA) is an integrated and synergistic proposal assembling a group of VA investigators focused on improving AVF maturation failure for Veteran hemodialysis patients. The Overall Research Strategy is to elucidate mechanisms of AVF maturation failure in order to develop novel therapies to mitigate this unmet clinical need. The overall rationale for this CMA is that fibrotic venous remodeling influences intimal hyperplasia development and successful outward remodeling, and mitigating these biological problems could improve successful AVF maturation. Specifically, the CMA will define those mechanisms by which aging (Project 1), Type VIII collagen in smooth muscle cells (Project 2), and endothelial cell autophagy (Project 3) determines venous remodeling after AVF anastomosis. The overarching hypothesis of this CMA project is that the biology of AVF maturation is influenced by mechanisms regulating venous fibrotic remodeling. Specific to project 3, we will investigate the role of endothelial cell (EC) autophagy in fibrotic venous remodeling in AVF maturation. The mechanisms leading to AVF maturation failure are poorly understood; and the lack of therapies to treat this clinical problem in hemodialysis patients represents an unmet clinical need. Our central hypothesis is that impaired endothelial cell autophagy, after AVF creation, promotes venous fibrotic remodeling, leading to AVF maturation failure. We will address our central hypothesis with three specific aims: Specific Aim I: Demonstrate the role of EC autophagy in the setting of disturbed flow and its impact on profibrotic signaling, Specific Aim II: Demonstrate the role of EC autophagy in venous fibrosis and AVF remodeling, and Specific Aim III: Demonstrate the association of EC autophagy with venous fibrosis and AVF maturation.