Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula

ABSTRACT
Autologous arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis. However, high rate of
maturation failure due to inadequate blood flow in the outflow vein renders the fistula not useful for hemodialysis.
Neointimal hyperplasia and failure of outward remodeling are the major causes of AVF maturation failure which
is due to inflammation, proliferation, migration, and phenotypic changes of vascular smooth muscle cells
(VSMCs), and extracellular remodeling due to increased matrix metalloproteinases (MMPs). We discovered
increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1), TLR4 and related proteins
in the immature AV fistula. Based on our novel findings, the central hypothesis is that hemodynamic injury
during AVF creation induces inflammation to upregulate TREM-1 and TLR4 to enhance neointimal
hyperplasia and vascular remodeling, and antagonizing TREM-1 and TLR4 will enhance AVF maturation.
This hypothesis will be tested with the following Aims: Aim 1: Our corollary hypothesis predicts that the
administration of TREM-1 and TLR4 antagonists will prevent maturation failure of AVF in swine. We will
examine the effect of a potent inhibitory TREM-1 peptide in the AVF model in pigs. Since TREM-1 could
synergize with TLR4 to mediate the pathology of AVF maturation failure, effect of a potent TLR4 antagonist will
also be examined to prevent maturation failure of AVF. The outcome parameters will include neointimal
hyperplasia in the inflow and outflow segments in the AVF, angiography of the AVF, color Doppler ultrasound,
optical coherence tomography, and histology, immunostaining to analyze inflammation, expression of various
mediators and infiltration of macrophages and neutrophils, VSMC apoptosis, and vascular remodeling. Aim 2:
Our corollary hypothesis predicts that the TREM-1 and TLR4 antagonism inhibits inflammation and thus
prevents maturation failure of AVF by reducing the development of intimal hyperplasia and vascular
remodeling primarily due to inflammatory cells, cathepsin L, IL-8 and MMP-12. These studies will be
performed in the blood and isolated VSMCs of femoral artery and femoral vein of the pigs from Aim 1.
Mechanistic studies will examine the effect of TREM-1 and TLR4 inhibition in the presence of IL-8 on neutrophils,
monocyte-differentiated macrophages and VSMCs, and cathepsin L-mediated elastin and collagen degradation
in VSMCs, and the effect of elastin-derived peptides on monocyte differentiation into macrophages and VSMC
proliferation and migration. Additional mechanistic studies will include the link between TLR4 and TREM-1 in
promoting matrix remodeling, release of inflammatory cytokines from neutrophils and macrophages in the cross-
talk inducing phenotype switch in VSMCs and macrophage polarization.
The findings from this study will confirm if TREM-1 is a novel target for therapeutic intervention and extend
the knowledge to develop better molecules to antagonize TREM-1 and design phase I clinical trials.

Grant Number: 5R01HL147662-04
NIH Institute/Center: NIH
Principal Investigator: Devendra Agrawal