Late Neointimal Hyperplasia in Vein Grafts Expands via TGF‐β/CTGF Mediated Fibrosis

Abstract

IntroductionIn weeks to months following implantation, neointimal hyperplasia (NIH) in vein grafts (VG) transitions from a cellularized to decellularized phenotype. Inhibition of early cellular proliferation failed to improve long‐term VG patency. We have previously demonstrated that TGF‐β /CTGF pathways mediate a conversion of fibroblasts to myofibroblasts in the early VG (<2wks). We hypothesize that these similar pathways drive fibrosis observed in the late VG lesion.MethodsWithin rabbit VGs, real time RT‐PCR, Western blotting, and immunohistochemistry were used to examine TGF‐β /CTGF pathways in late (1‐6 month) NIH.ResultsAll 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 types I to II receptor ratio, SMAD2/3 phosphorylation, and CTGF production, persisted throughout the observation period. Increased matrix synthesis was accompanied by a temporal reduction of MMP2 (p=0.001) and 9 (p<0.001) activity.ConclusionVG NIH is characterized by a conversion from a pro‐proliferative to profibrotic morphology. Enhanced signaling via TGF‐β /CTGF coupled with reduced MMP activities promotes progressive fibrotic NIH expansion. Modulation of late TGF‐β /CTGF signaling may offer a novel therapeutic strategy to improve the long‐term VG durability.