Venous anastomotic intimal hyperplasia (VAIH) is the most prevalent cause of hemodialysis arteriovenous (AV) graft failure. The economic impact of AV access and its related morbidity approaches one billion dollars annually in the US. Previously, this laboratory has demonstrated that hemodynamic forces regulate key in vivo molecular and structural events in artery wall intimal hyperplasia. We will apply and extend this expertise to investigate the independent role(s) of turbulence-induced solid and fluid dynamic forces in inducing VAIH following AV graft implantation. The investigators have established a realistic experimental in vivo model of the human AV circuit and VAIH to test the following hypotheses: 1) VAIH is modulated by turbulence-induced vein wall vibration levels, with elevated vein wall vibration enhancing, and reduced vein wall vibration attenuating, VAIH; 2) This relationship is independent of regional variations in wall shear stress magnitude within venous anastomoses subjected to turbulent flow conditions; 3) Elevated vein wall vibration upregulates the level and activity of the extra-cellular regulatory kinase (ERK1/2) and the stress activated protein kinase (JNK and p38) required for transcriptional activation of the immediate early genes (IEGs) Egr-1, c-jun and c-fos involved in VSMC differentiation, proliferation, apoptosis and VAIH. To verify the proposed hypotheses we will correlate the degree and localization (transmural, circumferential, and axial) of the above-mentioned molecular and cellular events with the corresponding magnitude and spatial distribution of the venous anastomotic biomechanical variables under conditions of elevated and reduced levels of vein wall vibration. It is anticipated that the results of these novel investigations will provide seminal information regarding the pathogenesis and detection of AV grafts at risk for accelerated VAIH, and for the design of interventions to inhibit VAIH and extend patency of hemodialysis AV grafts.
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