Established neointimal hyperplasia in vein grafts expands via TGF-β-mediated progressive fibrosis

Abstract

In weeks to months following implantation, neointimal hyperplasia (NIH) in vein grafts (VGs) transitions from a cellularized to a decellularized phenotype. The inhibition of early cellular proliferation failed to improve long-term VG patency. We have previously demonstrated that transforming growth factor-β1 (TGF-β1)/connective tissue growth factor (CTGF) pathways mediate a conversion of fibroblasts to myofibroblasts in the early VG (<2 wk). We hypothesize that these similar pathways drive fibrosis observed in the late VG lesion. Within rabbit VGs, real-time RT-PCR, Western blot analysis, ELISA, and immunohistochemistry were used to examine TGF-β/CTGF pathways in late (1–6 mo) NIH. All VGs exhibited a steady NIH growth ( P = 0.006) with significant reduction in cellularity ( P = 0.01) over time. Substantial TGF-β profibrotic activities, as evidenced by enhanced TGF-β1 activation, TGF-β receptor types I (activin receptor-like kinase 5)-to-II receptor ratio, SMAD2/3 phosphorylation, and CTGF production, persisted throughout the observation period. An increased matrix synthesis was accompanied by a temporal reduction of matrix metalloproteinase-2 ( P = 0.001) and -9 ( P < 0.001) activity. VG NIH is characterized by a conversion from a proproliferative to a profibrotic morphology. An enhanced signaling via TGF-β/CTGF coupled with reduced matrix metalloproteinase activities promotes progressive fibrotic NIH expansion. The modulation of late TGF-β/CTGF signaling may offer a novel therapeutic strategy to improve the long-term VG durability.