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

Abstract

BackgroundArteriovenous fistula (AVF) postoperative stenosis is a persistent healthcare problem for hemodialysis patients. We have previously demonstrated that fibrotic remodeling contributes to AVF non-maturation and lysyl oxidase (LOX) is upregulated in failed AVFs compared to matured. Herein, we developed a nanofiber scaffold for the periadventitial delivery of β-aminopropionitrile (BAPN) to determine whether unidirectional periadventitial LOX inhibition is a suitable strategy to promote adaptive AVF remodeling in a rat model of AVF remodeling.MethodsBilayer poly (lactic acid) ([PLA)-]- poly (lactic-co-glycolic acid) ([PLGA)] scaffolds were fabricated with using a two-step electrospinning process to confer directionality. BAPN-loaded and vehicle control scaffolds were wrapped around the venous limb of a rat femoral-epigastric AVF during surgery. AVF patency and lumen diameter were followed monitored using Doppler ultrasound surveillance and flow was measured before euthanasia. AVFs were harvested after 21 days for histomorphometry and immunohistochemistry. AVF compliance was measured using pressure myography. RNA from AVF veins was sequenced to analyze changes in gene expression due to LOX inhibition.ResultsBilayer periadventitial nanofiber scaffolds extended BAPN release compared to the monolayer design (p < 0.005) and only released BAPN in one direction. Periadventitial LOX inhibition led to significant increases in AVF dilation and flow after 21 days. Histologically, BAPN trended toward increased lumen and significantly reduced fibrosis compared to control scaffolds (p < 0.01). Periadventitial BAPN reduced downregulated markers associated with myofibroblast differentiation including SMA, FSP-1, LOX, and TGF-β while increasing the contractile marker MYH11. RNA sequencing revealed differential expression of matrisome genes.ConclusionPeriadventitial BAPN treatment reduces fibrosis and promotes AVF compliance. Interestingly, the inhibition of LOX leads to increased accumulation of contractile VSMC while reducing myofibroblast-like cells. Periadventitial LOX inhibition alters the matrisome to improve AVF vascular remodeling.

Building a Scaffold for Arteriovenous Fistula Maturation: Unravelling the Role of the Extracellular Matrix

“…Both treatments decreased fibrosis and shear stress and improved flow volume and distensibility in the AVF. A follow-up rat study showed that a BAPN-loaded PGLA nanofibre scaffold around the AVF promotes OR, prevents adventitial fibrosis, and improves vascular compliance [ 109 ]. BAPN and LOX, however, are both involved in cross-linking of collagen as well as elastin fibres and are, therefore, not exclusively related to collagen [ 110 ].…”

Regulation of vascular remodeling by immune microenvironment after the establishment of autologous arteriovenous fistula in ESRD patients

“…Therefore, fibrotic remodeling and NIH, which in combination significantly increase the risk of AVF failure ( 14 ). Our previous study have shown that in the inferior vena cava of adenine-induced chronic kidney disease rats with aortocaval fistulas, in addition to the disordered EC and SMC, inflammatory cells such as macrophage (Mφ) are also present in the major cellular components of NIH ( 15 ).…”

“…AVF fibrosis can be attributed to excessive extracellular matrix (ECM) synthesis by activated VSMAs and myofibroblasts and/or insufficient ECM degradation by matrix metalloproteinases (MMP). Excessive fibrosis may reduce vessel wall compliance, and AVF patients with intermediate fibrosis have less increase in venous diameter during reconstruction (13). When the vessel wall loses compliance due to excessive ECM deposition, the NIH becomes obstructive (possibly less compressible under high blood flow) and stenotic.…”