Prevention of Venous Neointimal Hyperplasia by a Multitarget Receptor Tyrosine Kinase Inhibitor

Abstract

Background/Aims: Venous neointimal hyperplasia (NH) is the predominant cause of stenosis in hemodialysis arteriovenous grafts (AVG), but there is currently no clinically used therapy to prevent NH. Methods: A porcine AVG model was used to identify potential pharmacological targets to prevent NH. Sunitinib, a broad-spectrum tyrosine kinase inhibitor, was examined as a potential anti-NH drug utilizing in vitro and ex vivo models. Results: In an in vivo porcine model, PDGF, VEGF and their receptors PDGFR-α and VEGFR-2 were upregulated at the venous anastomosis within 2 weeks after AVG placement, with NH development by 4 weeks. Sunitinib inhibited PDGF-stimulated proliferation, migration, phosphorylation of MAPK and PI3K/Akt proteins and changes in the expression of cell-cycle regulatory proteins in vascular smooth-muscle cells as well as VEGF-stimulated endothelial cell proliferation in vitro. In an ex vivo model, significant NH was observed in porcine vein segments perfused for 12 days under pathological shear stress. Sunitinib (100 n<smlcap>M</smlcap>) inhibited NH formation, with the intima-to-lumen area ratio decreasing from 0.45 ± 0.25 to 0.04 ± 0.02 (p < 0.05) with treatment. Conclusion: These findings demonstrate sunitinib to be a potential NH-preventive drug as well as the utility of an ex vivo model to investigate pharmacotherapies under pathophysiological flow conditions.

Natural Vascular Scaffolding Treatment Promotes Outward Remodeling During Arteriovenous Fistula Development in Rats

“…Rats were euthanized at 1 week ( n = 3–4 per group) or 4 weeks ( n = 6–9 per group). The AVF vessels were harvested en bloc and placed in buffered zinc formalin for 48 h. The fixed tissues were embedded in paraffin and serially sectioned in 5 μm sections, following the standard histology procedures as previously described by us ( Kwon et al, 2015 ; Shiu et al, 2016 ; Cho et al, 2020 ). Sections were stained with hematoxylin and eosin (H&E) and Verhoeff-Van Gieson (VVG) stain for subsequent morphometric analysis.…”

Reduced Expression of Glutathione S-Transferase α 4 Promotes Vascular Neointimal Hyperplasia in CKD

“…28 However, formation of neointima from proliferation of SMCs is a hallmark of AVF failure. 29,30 Among a host of multiple factors, CKD is one of the most important factors that accelerates AVF failure. Hence, understanding the mechanisms leading to SMCs accumulating in the forming neointima is critical for designing preventive therapeutic strategies.…”