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

Arteriovenous fistulas (AVFs) are the preferred vascular access for hemodialysis patients with end stage kidney disease (ESKD). A large proportion of AVFs (30-60%) created in the United States fail to successfully mature (i.e., lack sufficiently large lumen and blood flow) and require assisted maturation for dialysis use. 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. This BCCMA, entitled “Cardiovascular Remodeling following Arteriovenous Fistula Creation”, is an integrated and synergistic proposal assembling a group of Veteran Affairs 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 BCCMA is that fibrotic venous remodeling promotes intimal hyperplasia development to restrict lumen area for blood flow, and mitigating these biological problems could improve successful AVF maturation. The specific aims of this BCCMA will define mechanisms by which senescence and aging in endothelial cells (EC) (Project 1), Type VIII collagen in smooth muscle cells (SMC) (Project 2), and autophagy in EC (Project 3) determine venous remodeling after AVF creation. The overarching hypothesis of this BCCMA project is that the biology of AVF maturation is influenced by mechanisms regulating venous fibrotic remodeling. In Project 1, entitled “Aging Contributes to Adverse Arteriovenous Fistula Remodeling”, we aim to advance our understanding of senescence- and aging-related AVF maturation failure and develop treatments to enhance AVF maturation. Our central hypothesis is that disturbed flow decreases sirtuin 1 (SIRT1) and the shelterin protein telomeric repeat binding factor 2 (TRF2) to induce senescence-associated secretory phenotype (SASP) in EC, which results in profibrotic signaling to cause fibrosis and AVF maturation failure. We also hypothesize that chronological aging enhances EC SASP transformation under disturbed flow. We will test our hypotheses with three specific aims. Aim I: Demonstrate the roles of endothelial SIRT1 and TRF2 in disturbed flow-induced SASP and profibrotic signaling (in vitro aim). Aim II: Demonstrate the causality of endothelial SIRT1 and TRF2 in SASP, venous fibrosis, and AVF remodeling in mice (in vivo aim). Aim III: Demonstrate the associations of endothelial SIRT1-TRF2-SASP levels with venous fibrosis and AVF maturation in hemodialysis patients (human aim). The knowledge gained by completing the proposed aims will help to identify novel pharmaceutical targets for the prevention/treatment of AVF maturation failure.