Stenosis at the graft-vein anastomosis due to neointimal hyperplasia (NH) is the predominant cause of failure of arteriovenous grafts (AVGs) used for hemodialysis. Currently, there are no clinical therapies that significantly prevent or tret primary AVG NH. Shunting of arterial blood flow directly into the vein greatly alters the hemodynamics in the vein. Consequently, the fluid shear stress (FSS) and wall circumferential stress (WCS) at the NH-susceptible sites of AVGs are markedly altered. We propose that these hemodynamic changes are major contributors to NH development at the venous anastomosis of AVGs. This project aims to understand the hemodynamic regulation of NH development in AVGs. Detailed FSS and WCS in the AVG setting are not yet fully understood. We will use state-of-the-art image-based computational mechanics to characterize these stresses, and apply these data to design experiments to delineate mechanotransduction pathways. We will focus on i) the roles of two receptor tyrosine kinases (RTKs), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), as major mechanosensors in the pathogenesis of NH;and ii) the role of the transcription factor E twenty-six-1 (Ets-1) as the primary effector activated by RTK, leading to NH formation. Our proposal is based on our preliminary findings that i) VEGFR, PDGFR and Ets-1 are up-regulated in NH-susceptible sites in a porcine AVG model;ii) the RTK inhibitor sunitinib inhibits Ets-1 expression and NH development in a perfused vein organ culture model;iii) NH formation is reduced by Ets-1 inhibition in a rat model of carotid artery balloon injury and a mouse model of native arteriovenous fistula. Our hypotheses are as follows: i) The activation of RTK and Ets-1 is initiated by increases in FSS and WCS, as a result of increased blood flow and wall distention respectively, at the juxta-anastomotic vein segment of the AVG. ii) VEGFR and PDGFR are the primary mechanosensors in vascular endothelial cells and smooth muscle cells, respectively, that mediate Ets-1 activation by FSS and WCS. iii) RTK activation followed by Ets-1 activation is a critical event in NH formation in the AVG. There are three Specific Aims: i) Understand differences in the mechanical environment between the NH- susceptible and NH-resistant sites of AVG in a porcine model. ii) Determine in a perfused vein culture model whether increased FSS or WCS enhances RTK and Ets-1 activation and subsequently NH formation. iii) Explore whether RTK and Ets-1 mediate NH formation in a porcine AVG model. Delineation of the RTK- and Ets-1-dependent mechanotransduction pathways and exploration of the roles of these pathways in NH formation is novel. The results have the potential for broad applications in other vascular pathological conditions where there is altered blood flow, including AV fistulas. The perfused organ culture system can be used to investigate pharmacological therapies under relevant flow conditions.
Surgically-created blood conduits that are used for chronic hemodialysis are the lifeline for kidney failure patients, but unfortunately these conduits often fil as a result of excessive tissue growth, blocking blood flow. Currently, no clinical therapies are available to significantly prevent or treat this tissue overgrowth. The successful completion of this project will provide a sound background for the development of an innovative strategy to prevent hemodialysis blood conduit failure.
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