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

2009 ◽  
Vol 297 (4) ◽  
pp. H1200-H1207 ◽  
Author(s):  
Zhihua Jiang ◽  
Ming Tao ◽  
Kerri A. Omalley ◽  
Danlu Wang ◽  
C. Keith Ozaki ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Neointimal Hyperplasia ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Matrix Metalloproteinase 2 ◽  
Vein Grafts

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.

TGF-β- and CTGF-mediated fibroblast recruitment influences early outward vein graft remodeling

2007 ◽  
Vol 293 (1) ◽  
pp. H482-H488 ◽  
Author(s):  
Zhihua Jiang ◽  
Peng Yu ◽  
Ming Tao ◽  
Chessy Fernandez ◽  
Cristos Ifantides ◽  
...  
Keyword(s):  
Growth Factor ◽  
Vein Graft ◽  
Transforming Growth Factor ◽  
Mechanical Load ◽  
Wall Stress ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Vein Grafts ◽  
Circumferential Wall Stress ◽  
The Impact

Luminal shearing forces have been shown to impact both geometric remodeling and the development of intimal hyperplasia. Less well studied is the influence of intramural wall stresses on vessel growth and adaptation. Using a vein graft-fistula configuration to isolate the impact of circumferential wall stress, we identify the reorganization of adventitial myofibroblasts as the dominant histological event that limits early outward remodeling of vein grafts in response to elevated wall stress. We hypothesize that increased production of transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) induces recruitment of myofibroblasts, promotes adventitial reorganization, and limits early outward remodeling in response to increased intramural wall stress. Vein grafts with a distal arteriovenous fistula in the neck of rabbits were constructed, resulting in a fourfold differential in circumferential wall stress. Using this model, we demonstrate 1) elevated wall stress augments the production of TGF-β and CTGF, 2) increased TGF-β expression and CTGF expression are correlated with the enhanced differentiation from fibroblasts to myofibroblasts, as evidenced by the significant increase in the α-actin-positive cells in adventitia, and 3) the levels of TGF-β, CTGF, and α-actin are inversely correlated with the magnitude of outward remodeling of the graft wall. Increased wall stress after vein graft implantation appears to induce a TGF-β- and CTGF-mediated recruitment of adventitial fibroblasts and a conversion to a myofibroblast phenotype. Although important in the maintenance of wall stability in the face of an increased mechanical load, this adventitial adaptation limits early outward remodeling of the vein conduit and may prove deleterious in maintaining long-term vein graft patency.

High Glucose Decreases Matrix Metalloproteinase-2 Activity in Rat Mesangial Cells via Transforming Growth Factor-β1

2001 ◽  
Vol 9 (4) ◽  
pp. 249-257 ◽  
Author(s):  
Rekha Singh ◽  
Ruo Hua Song ◽  
Nahid Alavi ◽  
Alfredo A. Pegoraro ◽  
Ashok K. Singh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β ◽  
Matrix Metalloproteinase 2

The Control of Matrix Metalloproteinase-2 Expression in Normal and Keratoconic Corneal Keratocyte Cultures

2000 ◽  
Vol 10 (4) ◽  
pp. 276-285 ◽  
Author(s):  
B.T. Parkin ◽  
V.A. Smith ◽  
D.L. Easty
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Early Phase ◽  
Transforming Growth Factor ◽  
Polyacrylamide Gel Electrophoresis ◽  
Transforming Growth Factor Β ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Dot Blot ◽  
Corneal Keratocytes

Purpose Early phase keratoconic comeas and their cultured keratocytes abnormally produce the Mr 62,000 form of the matrix metalloproteinase-2 (MMP-2). It is known that platelet derived growth factor (PDGF) and transforming growth factor-β (TGF-β) are involved in the regulation of MMP activity and tissue inhibitor of metalloproteinase (TIMP) production in non-ocular tissues. The purpose of this enquiry was to determine whether these growth factors also play a role in the activity and/or production of corneal MMP-2 and TIMP, and whether their activity could account for the existence of the Mr 62,000 form of MMP-2 in keratoconic corneas. Methods Confluent cultures of normal and early-phase keratoconic corneal keratocytes were established and incubated in serum-free media in the presence or absence of PDGF and TGF-β. The proteins secreted by these cells over periods of 7 days were harvested for analysis. The total protein produced was determined spectrophotometrically. MMP-2 was visualised by SDS-gelatin polyacrylamide gel electrophoresis and assayed using radiolabelled type IV collagen as substrate. The enzyme inhibitors, TIMP-1 and TIMP-2, were quantified by dot blot immunoassay. Results The addition of PDGF or TGF-β to the culture medium of keratoconic corneal keratocytes had no significant effect on overall protein production, MMP-2 activity or on the amounts of TIMP-1 and TIMP-2 secreted. These observations also applied to normal corneal keratocytes, with the exception that PDGF induced expression of the Mr 62,000 species of MMP-2. Conclusions PDGF may be involved in the production of the Mr 62,000 species of MMP-2 that is abnormally produced by early-phase keratoconic corneal keratocytes.

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