Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 297, Issue 4, Pages H1200-H1207Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00268.2009
Keywords
transforming growth factor-beta; stenosis; connective tissue growth factor
Funding
- National Heart, Lung, and Blood Institute [1R01-HL-079135-01, 1K08-HL-04070-01A1]
- Lifeline Foundation
- American Heart Association Scientist Development
- James and Esther King Biomedical Research Program
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Jiang Z, Tao M, Omalley KA, Wang D, Ozaki CK, Berceli SA. Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis. Am J Physiol Heart Circ Physiol 297: H1200-H1207, 2009. First published July 17, 2009; doi: 10.1152/ajpheart.00268.2009.-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-beta(1) (TGF-beta(1))/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-beta/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-beta profibrotic activities, as evidenced by enhanced TGF-beta(1) activation, TGF-beta 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-beta/CTGF coupled with reduced matrix metalloproteinase activities promotes progressive fibrotic NIH expansion. The modulation of late TGF-beta/CTGF signaling may offer a novel therapeutic strategy to improve the long-term VG durability.
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