Regulation of venous remodeling and arteriovenous fistula patency by the matricellular protein Tenascin-C

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PROJECT SUMMARY/ABSTRACT End-stage renal disease (ESRD) is a serious public health issue with increasing mortality worldwide; the United States Renal Data System reported that over 740,000 people were affected in the U.S. in 2017. However, only ~30% of all patients with ESRD receive kidney transplants, the most desirable option, leaving the majority of patients to be treated with hemodialysis. Unfortunately, AVF is the procedure with the worst patency among all procedures performed by vascular surgeons. AVF fail to mature, that is dilate and thicken, in ~20-50% of cases, resulting in “early failure” requiring reinterventions to promote successful maturation. In the AVF that do mature, “late failure” occurs in ~35-40% during the first year due to neointimal hyperplasia (NIH) that leads to excessive wall thickening, resulting in AVF occlusion leading to patient suffering, morbidity and mortality. Women have even worse rates of AVF maturation compared to men, resulting in reduced AVF utilization. This project proposes to use our established aortocaval mouse model to investigate why women have worse AVF outcomes and to investigate the role of tenascin-C (TnC) during venous remodeling; our preliminary data show TnC expression is absent in adult mouse veins but is expressed in the vein wall after AVF creation. The overarching goal of this proposal is to investigate whether manipulation of TnC function may serve as a novel therapeutic strategy to improve AVF patency. The first Aim of this project determines differences in cell function and/or reduced AVF maturation and patency between sexes in wild-type and TnC- KO mice. Our preliminary data shows that AVF creation in mice results in hemodynamic differences between sexes, as well as differential expression of proteins, some of which are directly influenced by TnC. The second Aim determines differences in IVC mechanical properties between sexes in wild-type and TnC-KO mice at baseline and after AVF creation, and assesses the role of TnC in extracellular matrix (ECM) composition. I will also determine how manipulation of TGF-b1 signaling influences TnC-induced NIH, since TGF-b1, whose sustained expression leads to NIH, induces TnC expression that creates a positive feedback loop resulting in increased levels of both TGF-b1 and TnC. Therefore, this project will determine the role of TnC in venous remodeling after AVF creation and identify critical differences between sexes responsible for differences in AVF outcomes. Accomplishing the aims of this project will show new strategies to improve AVF patency rates that reduce complications and healthcare costs as well as improve quality of life for patients suffering from ESRD.