Inhibition of Lysyl Oxidase with β-aminopropionitrile Improves Venous Adaptation after Arteriovenous Fistula Creation

Abstract

Background: The arteriovenous fistula (AVF) is the preferred hemodialysis access for end-stage renal disease (ESRD) patients. Yet, establishment of a functional AVF presents a challenge, even for the most experienced surgeons, since postoperative stenosis frequently occludes the AVF. Stenosis results from the loss of compliance in fibrotic areas of the fistula which turns intimal hyperplasia into an occlusive feature. Fibrotic remodeling depends on deposition and crosslinking of collagen by lysyl oxidase (LOX), an enzyme that catalyzes the deamination of lysine and hydroxylysine residues, facilitating intra/intermolecular covalent bonds. We postulate that pharmacological inhibition of lysyl oxidase (LOX) increases postoperative venous compliance and prevents stenosis in a rat AVF model. Methods: LOX gene expression and vascular localization were assayed in rat AVFs and human pre-access veins, respectively. Collagen crosslinking was measured in humans AVFs that matured or failed, and in rat AVFs treated with β-aminopropionitrile (BAPN), an irreversible LOX inhibitor. BAPN was either injected systemically or delivered locally around rat AVFs using nanofiber scaffolds. The major endpoints were AVF blood flow, wall fibrosis, collagen crosslinking, and vascular distensibility. Results: Non-maturation of human AVFs was associated with higher LOX deposition in pre-access veins (N=20, P=0.029), and increased trivalent crosslinks (N=18, P=0.027) in human AVF tissues. Systemic and local inhibition of LOX increased AVF distensibility, while reducing wall fibrosis and collagen crosslinking in rat fistulas. Conclusions: Our results demonstrate that BAPN-mediated inhibition of LOX significantly improves vascular remodeling in experimental fistulas.

Localized Perivascular Therapeutic Approaches to Inhibit Venous Neointimal Hyperplasia in Arteriovenous Fistula Access for Hemodialysis Use

“…β-aminopropionitrile (BAPN) is an irreversible inhibitor of lysyl oxidase, an enzyme that catalyzes the deamination of lysine and hydroxylysine residues, an essential step in the formation of covalent cross-links in ECM proteins. Hernandez et al found significantly higher lysyl oxidase deposition (5.3% versus 1.69% of vascular wall area; p = 0.03) and trivalent cross-linking density (0.061 µmol/mg versus 0.041 µmol/mg of dry tissue weight; p = 0.03) in veins of AVFs that failed versus those that successfully matured [ 58 ]. They hypothesized that BAPN administration could improve AVF patency and found that local delivery of BAPN in rat AVFs through an electrospun scaffold significantly decreased wall fibrosis (34.79 ± 3.83 versus 47.17 ± 8.65%; p = 0.03) and demonstrated a nonsignificant trend toward increased blood flow (34.03 ± 17.32 versus 24.80 ± 7.60 mL/min; p = 0.28) versus vehicle-loaded scaffolds at day 21 [ 58 ].…”

“…Hernandez et al found significantly higher lysyl oxidase deposition (5.3% versus 1.69% of vascular wall area; p = 0.03) and trivalent cross-linking density (0.061 µmol/mg versus 0.041 µmol/mg of dry tissue weight; p = 0.03) in veins of AVFs that failed versus those that successfully matured [ 58 ]. They hypothesized that BAPN administration could improve AVF patency and found that local delivery of BAPN in rat AVFs through an electrospun scaffold significantly decreased wall fibrosis (34.79 ± 3.83 versus 47.17 ± 8.65%; p = 0.03) and demonstrated a nonsignificant trend toward increased blood flow (34.03 ± 17.32 versus 24.80 ± 7.60 mL/min; p = 0.28) versus vehicle-loaded scaffolds at day 21 [ 58 ]. These findings indicate that local BAPN administration via perivascular scaffolds may improve AVF maturation, but more studies are needed to substantiate this hypothesis.…”

Vein morphometry in end-stage kidney disease: Teasing out the contribution of age, comorbidities, and vintage to chronic wall remodeling

“…Vascular fibrosis underlies post-thrombotic syndrome after deep vein thrombosis ( 7 ). Excessive postoperative fibrosis also plays a significant role in maturation failure of newly created AVFs, which is further exacerbated by concurrent IH ( 8 , 17 ). The chronic and acute/postoperative distinctions are particularly important to the study of vascular remodeling.…”

Periadventitial β-aminopropionitrile-loaded nanofibers reduce fibrosis and improve arteriovenous fistula remodeling in rats

“…We previously disclosed a link between postoperative fibrosis and AVF non-maturation (2) which is associated with increased lysyl oxidase (LOX) expression (3). LOX and its analogues, the LOX-like family, catalyze covalent crosslinking of collagen and elastin monomers, the primary constituents of the vascular ECM, to form supramolecular bundles that impart the characteristic biomechanics of healthy vasculature.…”

“…LOX also interacts with extracellular signaling molecules and nuclear transcription factors to directly influence cell phenotype (5). Aberrant LOX activity has been associated with increased in tissue stiffness, fibrosis, and pathological cancer-like microenvironments (3,6,7).…”