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