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TRANSLATIONAL PHYSIOLOGY

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

¹University of Florida College of Medicine and the Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida; and ²Harvard Medical School Brigham and Women's Hospital, Boston, Massachusetts

Submitted March 19, 2009 ; accepted in final form July 14, 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-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.

transforming growth factor-β; stenosis; connective tissue growth factor

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				J. Wu and C. Zhang Neointimal hyperplasia, vein graft remodeling, and long-term patency Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1194 - H1195. [Full Text] [PDF]