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Late Neointimal Hyperplasia in Vein Grafts Expands via TGF‐β/CTGF Mediated Fibrosis
Author(s) -
Jiang Zhihua,
Tao Ming,
Omalley Kerri A,
Wang Danlu,
Ozaki C. Keith,
Berceli Scott A
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.312.3
Subject(s) - ctgf , fibrosis , transforming growth factor , myofibroblast , medicine , matrix metalloproteinase , cancer research , hyperplasia , endocrinology , chemistry , growth factor , signal transduction , pathology , receptor , biochemistry
In 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. Methods Within rabbit VGs, real time RT‐PCR, Western blotting, and immunohistochemistry were used to examine TGF‐β /CTGF pathways in late (1‐6 month) NIH. Results 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 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. Conclusion VG 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.