Tenascin-C: A regulator of venous remodeling following aortocaval fistula creation

Author

Luis Gonzalez, Yale University Graduate School of Arts and SciencesFollow

Date of Award

Fall 2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Dardik, Alan

Abstract

End-stage kidney disease (ESKD) represents a growing medical problem globally with a high burden to patients. In the United States alone more than 740,000 individuals have ESKD and are primarily dependent on hemodialysis for treatment. For patients who require hemodialysis, arteriovenous fistulae (AVF) are the preferred mode of vascular access due to their superior patency rates and reduced infection rates when compared to grafts or catheters. However, the lifespan of an AVF is limited by several complications, which includes neointimal hyperplasia (NIH) and thrombosis. Loss of AVF patency at 1-year ranges ~40-50%. Successful AVF maturation is characterized by venous wall remodeling in response to increased cell proliferation and changes in extracellular matrix (ECM) composition resulting in vessel wall dilation and thickening. AVF maturation is necessary for repeated cannulation for hemodialysis, however, promoting wall thickening for structural strength without exuberant thickening and the development of neointimal hyperplasia (NIH) is a current challenge.The ECM is a complex network of molecules secreted by cells, which is essential for providing structural support and facilitating cell processes such as adhesion, migration, and survival. Endogenous molecules, including matricellular proteins, have been shown to induce inflammation via toll-like receptor (TLR) activation to drive an immune response in response to tissue injury. Tenascin-C (TnC), the founding member of the matricellular tenascin family, is a large multi-domain ECM glycoprotein that is abundantly expressed during embryonic development but exhibits limited expression during adulthood. It is transiently elevated at sites of tissue injury and is persistently expressed in chronic inflammatory diseases, driving cytokine synthesis via activation of TLR4 by its C-terminus fibrinogen-like globe (FBG) domain. TnC pro-inflammatory role has been implicated in the pathogenesis of a variety of chronic inflammatory diseases characterized by upregulated TnC locally and systemically. TnC is highly induced following AVF creation and has been implicated in regulating ECM deposition and remodeling, promoting cell proliferation and migration, and modulating the immune response. Following AVF creation, TnC expression is both temporally and spatially controlled, where maximal expression is observed at post-operative day (POD) 7 and at sites of mechanical injury and venous remodeling. Absence of TnC resulted reduced levels of cell proliferation and collagen deposition resulting in thinner walls. Additionally, during the patency phase (POD 21-42) TnC was observed to be highly expressed in fistulae that failed compared to those that remain patent. High expression of TnC coincided with reduced expression of thrombomodulin (THBD) potentially leading to the promotion of a thrombogenic environment and resulting in AVF occlusion. However, although TnC-/- mice had reduced levels of wall thickening they paradoxically failed more often than their wild-type (WT) littermates. This is believed to be driven in response to differences in the immune response in the presence or absence of TnC. TnC can alter macrophage polarization via TLR4 and V3 integrin signaling promoting to M1 macrophage polarization, while simultaneously inhibiting M2 macrophage polarization via inhibition of IRF4, a potent driver of M2 macrophage polarization. Differences in macrophage subsets may drive AVF failure via a distinct mechanism by which M2 macrophages express higher levels of Tissue Factor (TF), a potent pro-thrombotic molecule, generating a nidus where thrombosis and ultimately occlusion can occur. The contrasting finding that both the presence and absence of TnC can promote AVF occlusion may be attributable to the diverse set of TnC isoforms that can be expressed during the pathological progression of the disease. The work described here utilized an aortocaval fistula puncture model in combination with TnC-/- mice to investigate the role of TnC as a driver of venous remodeling and potentially AVF occlusion.

Recommended Citation

Gonzalez, Luis, "Tenascin-C: A regulator of venous remodeling following aortocaval fistula creation" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1239.
https://elischolar.library.yale.edu/gsas_dissertations/1239