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Targeting Endothelial Kruppel-Like Factor 2 (KLF2) in Arteriovenous

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Targeting Endothelial Krüppel-like Factor 2 (KLF2) in Arteriovenous Fistula Maturation Failure A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Biomedical Engineering Program Department of Biomedical Engineering College of Engineering and Applied Science 2018 by Keith Louis Saum B.S., Wright State University, 2012 Dissertation Committee: Albert Phillip Owens III, Ph.D. (Committee Chair) Begona Campos-Naciff, Ph.D Christy Holland, Ph.D. Daria Narmoneva, Ph.D. Prabir Roy-Chaudhury, M.D., Ph.D Charuhas Thakar, M.D. Abstract The arteriovenous fistula (AVF) is the preferred form of vascular access for hemodialysis. However, 25-60% of AVFs fail to mature to a state suitable for clinical use, resulting in significant morbidity, mortality, and cost for end-stage renal disease (ESRD) patients. AVF maturation failure is recognized to result from changes in local hemodynamics following fistula creation which lead to venous stenosis and thrombosis. In particular, abnormal wall shear stress (WSS) is thought to be a key stimulus which alters endothelial function and promotes AVF failure. In recent years, the transcription factor Krüppel-like factor-2 (KLF2) has emerged as a key regulator of endothelial function, and reduced KLF2 expression has been shown to correlate with disturbed WSS and AVF failure. Given KLF2’s importance in regulating endothelial function, the objective of this dissertation was to investigate how KLF2 expression is regulated by the hemodynamic and uremic stimuli within AVFs and determine if loss of endothelial KLF2 is responsible for impaired endothelial function. We tested the hypothesis that suppression of endothelial KLF2 by disturbed WSS or uremic solutes promotes endothelial dysfunction, and therapies which target these mechanisms could be used to induce KLF2 expression and improve AVF maturation. We first investigated the impact of abnormal WSS and the uremic milieu on KLF2 expression in cultured endothelial cells. Utilizing serum from pigs with chronic renal insufficiency, we demonstrated that endothelial KLF2 was suppressed following exposure to uremic serum. Through a series of experiments, this response was linked to the action of advanced glycation end-products (AGEs) and other protein- bound solutes which accumulated in ESRD. However, further studies demonstrated that the application of arterial WSS attenuated the effect of uremic serum on endothelial KLF2 expression. i We examined if loss of KLF2 was associated with changes in endothelial function in vivo. Using an endothelial-specific KLF2 deficient mouse, we observed impaired flow-mediated dilation (FMD) in uremic mice deficient in endothelial KLF2. Mechanistic studies revealed that impaired FMD in endothelial-deficient KLF2 mice was due to reduced nitric oxide availability. Furthermore, suppression of KLF2 was found to increase reactive oxygen species and leukocyte adhesion in cultured endothelial cells following exposure to uremic serum. Together, these observations suggested that uremia may exacerbate AVF failure in regions of abnormal WSS by synergistically suppressing endothelial KLF2. Finally, we attempted to translate these findings into a clinical therapy to promote KLF2 expression and improve AVF maturation. Utilizing computational fluid dynamics and microfabrication techniques, we designed, fabricated, and tested an endovascular implant capable of correcting abnormal WSS within an AVF. Computational and benchtop studies demonstrated the implant restored a physiological WSS profile in the draining vein. Implantation into a porcine AVF model resulted in increased KLF2 expression within the AVF vein at 28 days, but device thrombosis was observed. Further work is needed to optimize this therapeutic approach and access its impact on AVF outcomes. Overall, these data suggest loss of KLF2 in ESRD may promote endothelial dysfunction and subsequent AVF maturation failure. These findings may be beneficial for future studies targeting endothelial KLF2 during AVF maturation. ii © 2018 Keith Louis Saum ALL RIGHTS RESERVED iii Acknowledgements I would like to express my deep appreciation and gratitude to the many individuals who have helped and encouraged me on my path to becoming a physician-scientist. This dissertation would not have been possible without the help and support from all my current and former teachers, mentors, collaborators, and lab members. The following individuals deserve special acknowledgement for their contributions to my research, mentorship during my training, and constant support as I navigated the trials and tribulations of graduate school. First and foremost, I would like to thank my two primary research advisors, Dr. Prabir Roy-Chaudhury and Dr. Phillip Owens. Your willingness to take me into your laboratories as an MD/PhD student, introduce me to vascular biology research, and jointly mentor me throughout the course of my dissertation has been critical to my development as a scientist. Although different in mentoring styles, together you have guided me through the scientific process and honed my critical thinking skills. I enjoyed working with both of you and look forward to continued collaboration in the future. Second, I would like to thank Dr. Begona Campos-Naciff for her continual mentorship, knowledge, and support throughout my graduate studies. Without your motivation and encouragement I would not have applied to the Medical Scientist Training Program (MSTP) program following my second year of medical school. You saw the budding scientist in me and have graciously taken your time to teach me many lessons in science and life outside of the laboratory. Most importantly, you have constantly challenged me to reach my full potential and encouraged me to persevere in the face of hardship. I would also like to thank Dr. Christy Holland, Dr. Daria Narmoneva, and Dr. Charuhas Thakar for taking the time to be on my committee and provide feedback on my work. I benefitted iv greatly from discussions with them during the course of my research. Dr. Thakar has not only supported my interest in nephrology but has also helped ensure my research remains clinically relevant. Dr. Christy Holland has been a valuable resource for expertise into the areas of hemodynamics and ultrasound. Dr. Daria Narmoneva has provided keen insights on the biological impacts of my proposed work. During my time as a graduate student, I have been fortunate to work side-by-side in laboratories with some of the kindest, smartest, and most helpful people I have ever met. Dr. Diego Celdran Bonafonte has not only provided me with invaluable surgical expertise and experimental assistance, but also motivation in stressful times. Thank you to Shannon Jones, Adrien Mann, Nathan Robbins, Kelsey Conrad, and Hannah Russel for your daily help, discussions, and general camaraderie to break up the drudgery and dissipate stresses of graduate school. Many of the studies presented in this dissertation could not have been completed without the help of a multidisciplinary team of researchers. In addition to my fellow lab members mentioned above, I am indebted to the many collaborators that I have been privileged to work with and learn from over the past four years, including: Dr. Vesselin Shannov from the Department of Chemical and Materials Engineering; Dr. Liran Oren from the Department of Otolaryngology-Head and Neck Surgery; and Dr. Jack Rubinstein and Dr. Michael Tranter in the Division of Cardiovascular Health and Disease. My research successes would not have been possible without the committed support of the University of Cincinnati Medical Scientist Training Program (MSTP). I would also like to thank Dr. Gurjit Khurana Hershey, Dr. George Deepe, Dr. Kathryn Wikenheiser-Brokamp, Andrea DeSantis, and Amy Flanary for your dedication to the UC MSTP and for your tireless v efforts to create a nurturing environment that fosters both scientific and professional development. Lastly, thank you to my wonderful family and friends who have supported me throughout the ups and downs of my research and graduate education. My parents, Dan and Jeanie; my brothers, Scott and Craig; and my sister Jamie have provided endless love and encouragement. Most importantly, thank you to my wife Alyssa who has been a steady source of love and encouragement as I completed my graduate studies. Your unwavering support and patience has given me the strength and motivation to work hard and pursue my passions. I love you all very much. vi Organization of Dissertation This dissertation is composed of seven chapters and includes: an introduction to the field of hemodialysis vascular access and the clinical problem of arteriovenous fistula (AVF) maturation failure followed by a review of the relevant background literature (Chapter 1); a focused discussion of Krüppel-like Factor 2 and it role in endothelial cell function (Chapter 2); a description of the overall research approach and specific objectives of the dissertation (Chapter 3); a summary of the experimental results in the form of three scientific manuscripts (Chapters 4- 6); and a discussion of the major conclusions, limitations, and future directions of this work (Chapter 7). Chapter 1 begins by providing background about the burden of dialysis vascular access in end-stage renal disease (ESRD) and the pathogenesis of AVF maturation failure. The function and role of the endothelium in this problem is also reviewed, as is
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