Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis.
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.
Jiang
Zhihua
Z
Malcom Randall Veterans Affairs Medical Center, University of Florida College of Medicine, Gainesville, Florida, USA. jiangzh@surgery.ufl.edu
Tao
Ming
M
Omalley
Kerri A
KA
Wang
Danlu
D
Ozaki
C Keith
CK
Berceli
Scott A
SA
D000818:Animals; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D005355:Fibrosis; D006083:Graft Occlusion, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006965:Hyperplasia; D007601:Jugular Veins / Q000637:transplantation*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D042282:Microdissection; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011817:Rabbits; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D014654:Vascular Patency
D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9