Modulation of VSMC phenotype through the Insulin Receptor Substrate-1/Kruppel-like factor-4 signal transduction pathway: a Novel Target for AVF Dysfunction

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ABSTRACT Arteriovenous fistulae (AVF) are the preferred mode of permanent dialysis vascular access because of better long-term survival and reduced infection risks as compared to dialysis grafts and catheters. Unfortunately, AVFs have a maturation failure rate (defined as inadequate diameter and blood flow for dialysis) of over 50% at 6 months, which results in multiple additional interventions, and also a prolonged period of tunneled dialysis catheter dependency with all of its attendant complications. Thus, AVF maturation failure results in a very significant morbidity, mortality and economic cost. We and others have previously demonstrated that AVF maturation failure occurs due to a peri-anastomotic venous segment stenosis characterized by the de-differentiation of vascular smooth muscle cells (VSMC) into a synthetic phenotype, which then results in an aggressive venous neointimal hyperplasia. We have also developed a unique expertise both in the biology of AVF maturation (Roy-Chaudhury) and in the signal transduction mechanisms involved in VSMC phenotypic switching (Xi). We now plan to apply this combined experience and expertise to study the signal transduction pathways responsible for AVF maturation failure. The overarching central hypothesis of this proposal, therefore, is that environmental modulation of the insulin receptor substrate 1 (IRS-1) signal transduction pathway plays a key role in VSMC phenotype switching which then results in neointimal hyperplasia and AVF maturation failure. We plan to address this central hypothesis through three specific aims. Specific Aim 1 will assess the impact of different combinations of hyperglycemia, uremia and genetic manipulation of IRS-1 and Kruppel like factor 4 (KLF-4) on signal transduction/VSMC phenotypic switch pathways using explanted venous (jugular) and arterial (carotid) VSMC from C57Bl/6 WT control mice. Specific Aim 2 will assess the impact of this same upstream manipulation on signal transduction pathways, VSMC phenotypic switch and clinical, hemodynamic and histological endpoints, in a validated mouse model of AVF stenosis at 2, 7 and 14 days, post-surgery. Finally, Specific Aim 3 will assess the impact of nutlin-3, an inhibitor of MDM2 mediated ubiquitination of p-53 (which inhibits VSMC phenotypic switching) on the in-vitro and in-vivo end points described in Specific Aims 1 and 2 respectively. If successful, this novel, innovative, mechanism driven and pre-emptive approach to the intractable problem of AVF maturation failure, could significantly reduce the clinical morbidity and economic cost associated with this unmet clinical need.