Manipulating the matrix to improve arteriovenous fistula patency

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The preferred vascular access for hemodialysis uses an arteriovenous fistula (AVF) to increase blood flow through a vein. Successful adaptation of the venous conduit to the arterial-like fistula environment requires remodeling of the vein wall without excessive wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby increase successful clinical use of venous conduits. During the funding period, we used an innovative mouse AVF model to show that TGF-β signaling regulates venous adaptive remodeling to improve AVF patency; activation of both the smad2/3 (canonical) and tak1 (noncanonical) pathways regulate venous remodeling; and endothelial cell-targeted TGF-β inhibition regulates both collagen density and smooth muscle cell proliferation to improve AVF patency. We present exciting new data that: 1) expression of the matricellular protein tenascin-C (TnC) is greatly increased and colocalizes with the remodeling venous wall; 2) TnC regulates AVF patency and TGF-β signaling during venous remodeling; 3) TnC expression is not downregulated in failed AVF; and 4) TnC knockout mice have altered proportions of immune cells in the AVF wall. In addition, we have developed the mouse model further to incorporate chronic kidney disease (CKD) via 5/6-nephrectomy and these AVF faithfully recapitulate human AVF maturation. We hypothesize that modulating tenascin-C activity will alter venous remodeling, thereby improving AVF maturation and patency. We will use our translationally relevant in vivo model, an innovative tool using nanoparticles for local drug delivery, innovative methodology to analyze the cell composition within the AVF wall, as well as advanced next-generation analyses using transcriptomics techniques that are available at Yale, to test our innovative hypothesis with the following specific aims: Aim I: Determine sex differences in TnC expression during human AVF remodeling in vivo. Aim II: Determine whether TnC function mediates venous remodeling in mice with CKD. Aim III: Determine whether regulation of immune cells is a mechanism of TnC-mediated venous remodeling. A successful outcome of this investigation will have lasting impact by establishing whether TnC mediates venous remodeling, and thus whether regulating TnC activity is a valuable strategy for clinical translation to enhance AVF maturation. We will also determine whether reduced AVF maturation in women is due to sex differences in TnC function as well as in inflammation and/or immunity. We use an innovative strategy and novel tools and models to alter venous remodeling and thereby improve AVF maturation.