Advisory Committee Chair
Timmy Lee
Advisory Committee Members
Alecia K Gross
Ho-Wook Jun
Jennifer Pollock
Roger White
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Vascular access is the single most important component of the hemodialysis procedure and the arteriovenous fistula (AVF) is the most preferred type. However, 60% of AVFs created fail to mature successfully for dialysis use (AVF maturation failure). AVF maturation failure is primarily the result of 1) intimal hyperplasia formation (IH) and 2) poor vascular outward remodeling. Currently, a major unmet clinical need in the field is the lack of effective therapies to treat/prevent AVF maturation failure due to the poor understanding of molecular mechanisms. This proposal is designed to: 1) elucidate the pathologic significance of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signaling pathway on AVF maturation, 2) evaluate novel therapies/strategies to promote AVF maturation and 3) characterize rodent animal models important to elucidate mechanisms of vascular remodeling following vascular injury. AVF creation resulted in endothelial dysfunction in early time points and smooth muscle cell dysfunction in the later time point which accompanied by dysregulation of mediators that regulate NOS3 function and cGMP levels. By utilizing genetically modified mouse models we demonstrated that NO is critical for inhibition of IH and to promote vascular outward remodeling and hemodynamics following AVF creation which supported the rationale to provide NO as a therapy. Consequently, we demonstrate that perivascular delivery of novel NO releasing nanomatrix gel therapy can promote AVF maturation. iv Furthermore, we demonstrated that phosphodiesterase-5A (PDE5A-which degrade cGMP) expression is significantly increased following AVF creation and identified PDE5A as a drug target to modulate cGMP signaling. Consequently, inhibition of PDE5A with sildenafil resulted in increased blood flow and the outward expansion in AVF veins without affecting the level of intimal hyperplasia suggesting sildenafil treatment can promote AVF maturation by enhancing vascular outward remodeling. Finally, by utilizing a rat balloon angioplasty (intervention for AVF maturation failure) model we demonstrated that angioplasty accelerates intimal hyperplasia formation, increase collagen production and reduce NOS3 expression when compared to the control. We conclude that NO/cGMP signaling pathway plays a significant role in AVF maturation process and this thesis will provide the basis to develop novel therapeutic strategies to treat AVF maturation failure in hemodialysis patients.
Recommended Citation
Somarathna, Maheshika S., "The Role of Nitric Oxide and Cyclic Guanosine Monophosphate Signaling in Arteriovenous Fistula Maturation" (2022). All ETDs from UAB. 337.
https://digitalcommons.library.uab.edu/etd-collection/337