Immunolocalization and temporal distribution of cytokine expression during the development of vein graft intimal hyperplasia in an experimental model

Faries, Peter L.; Marin, Michael L.; Veith, Frank J.; Ramirez, José A.; Suggs, William D.; Parsons, Richard E.; Sánchez, Luis A.; Lyon, Ross T.

doi:10.1016/s0741-5214(96)70203-3

Cited by 56 publications

(41 citation statements)

References 24 publications

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“…The decrease in TIMP-2 levels correlates with increased vein graft expression of TNF-␣, a cytokine that downregulates TIMP-2 synthesis in vascular SMC (42). TNF-␣ also upregulates MMP-9 and MT1-MMP expression in SMCs (29) and has been implicated in the pathogenesis of vein graft intimal hyperplasia (5). Our experiments with cultured vascular SMC show that TNF-␣ does indeed upregulate MT1-MMP efficiently; however, TNF-␣ does not effect MMP-2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of inflammatory mediators are also involved in vascular remodeling. Tumor necrosis factor-␣ (TNF-␣), a cytokine implicated in the development of intimal hyperplasia and arterial remodeling (5), controls MMP-9 and MT1-MMP expression in a variety of cell types (28,30,40). Previous studies have described MMP-2 and MMP-9 expression in a porcine model of vein graft (37) and the use of MMP inhibitors to block intimal hyperplasia in an arterovenous-graft model (31).…”

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confidence: 99%

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Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2

Sharony¹,

Pintucci²,

Saunders³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Mignatti. Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2. Am J Physiol Heart Circ Physiol 290: H1651-H1659, 2006. First published November 11, 2005 doi:10.1152/ajpheart.00530.2005.-Matrix metalloproteinases (MMPs) play key roles in vascular remodeling. We characterized the role of inflammatory mediators and extracellular signal-regulated kinases (ERKs) in the control of arterialized vein graft expression of MMP-9, MMP-2, and membrane-type 1-MMP (MT1-MMP) and of the tissue inhibitor of metalloproteinases-2 (TIMP-2). For this purpose we used a canine model of jugular vein to carotid artery interposition graft and analyzed the vein grafts at various postoperative times (30 min to 28 days) using the contralateral vein as a control. To study the role of ERK-1/2, veins were incubated with the mitogen-activated protein kinase kinase (MEK-1/2) inhibitor UO126 for 30 min before being grafted. Vein graft extracts were analyzed for MMPs, TIMP-2, tumor necrosis factor-␣ (TNF-␣), polymorphonuclear neutrophil (PMN) infiltration, myeloperoxidase (MPO), and thrombin activity, and for ERK-1/2 activation. Vein graft arterialization resulted in rapid and sustained (8 h to 28 days) upregulation of vein graft-associated MMP-9, MMP-2, MT1-MMP, thrombin activity, and TNF-␣ levels with concomitant TIMP-2 downregulation. MMP-2 activation preceded MT1-MMP upregulation. PMN infiltration and vein graft-associated MPO activity increased within hours after arterialization, indicating a prompt, local inflammatory response. In cultured smooth muscle cells, both thrombin and TNF-␣ upregulated MT1-MMP expression; however, only thrombin activated MMP-2. Inhibition of ERK-1/2 activation blocked arterializationinduced upregulation of MMP-2, MMP-9, and MT1-MMP. Thus, thrombin, inflammatory mediators, and activation of the ERK-1/2 pathway control MMP and TIMP-2 expression in arterialized vein grafts.inflammation; mitogen-activated protein kinase; vascular remodeling VEIN GRAFT exposure to arterial circulation often results in intimal hyperplasia and medial hypertrophy, with eventual luminal stenosis and reocclusion. The process of vein graft stenosis involves migration and proliferation of smooth muscle cells (SMCs), along with excess deposition of extracellular proteins such as collagen (44).Matrix metalloproteinases (MMPs), a family of zinc-and calcium-dependent proteinases, collectively degrade all protein components of the extracellular matrix (ECM; 21). SMCs and macrophages in atherosclerotic and balloon-injured arteries express increased levels of MMP-9, MMP-2, and membranetype 1 metalloproteinase (MT1-MMP) (30). MMP-2 appears to have particular requirements for activation, entailing interaction with plasma membrane-tethered MMPs (the MT-MMPs) and formation of a trimolecular complex consisting of proMMP-2, MT-MMP, and tissue inhibitor of metalloproteinases-2 (TIMP-2) (38). MT1-MMP-bound MMP-2 is also activated by thrombin (23), plasmin, and neutrophil prote...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2

Sharony¹,

Pintucci²,

Saunders³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…In addition, however, these therapies must target recruitment to the graft of cells initially extrinsic to the graft, perhaps by reducing the inflammatory reaction associated with vein graft endothelial damage 22 and/or the chemokine/growth factor secretion by vein graft cells. 34 …”

Section: Discussionmentioning

confidence: 99%

Graft-Extrinsic Cells Predominate in Vein Graft Arterialization

Zhang

Freedman

Brian

et al. 2004

ATVB

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Objective-Vein graft disease involves neointimal smooth muscle cells, the origins of which are unclear. This study sought to characterize and quantitate vein graft infiltration by cells extrinsic to the graft in a mouse model of vein graft disease. Methods and Results-Inferior vena cava-to-carotid artery interposition grafting between C57Bl/6 and congenic ␤-galactosidase-expressing ROSA26 mice was performed. Vein grafts were harvested 6 weeks postoperatively and stained with X-gal. More than 60% of neointimal cells derived from the recipient, and 50% of these cells expressed smooth muscle ␣-actin.

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“…4,5 Inflammation is an important regulator of TM expression at both the transcriptional and posttranslational levels. Inflammatory cytokines, such as tumor necrosis factor-␣ and interleukin-1␤ that are released by activated leukocytes, potently inhibit TM gene expression.…”

mentioning

confidence: 99%

Wall Tension Is a Potent Negative Regulator of In Vivo Thrombomodulin Expression

Sperry

Deming

Bian

et al. 2003

Circulation Research

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Abstract-Thrombomodulin (TM), a key component of the anticoagulant protein C pathway, is a major contributor to vascular thromboresistance. We previously found that TM protein expression is dramatically reduced in autologous vein grafts during the first two weeks after implantation, coincident to a local inflammatory response, and remains suppressed for at least 6 weeks. To determine the proximate cause of TM loss, in vivo gene expression was quantified by real-time PCR. TM gene expression in vein grafts declined Ͼ85% during the first postoperative week and remained suppressed Ͼ55% at 6 weeks, accounting for the observed changes in protein expression. The effects of vein graft inflammation were evaluated in animals rendered leukopenic with vinblastine before graft implantation. Abrogating the local inflammatory response affected neither TM protein nor gene expression. To determine how hemodynamic forces might modulate TM expression, the surgical protocol was modified to alter blood flow and pressure-induced vessel distension. TM protein and gene expression did not correlate to changes in shear stress but highly correlated to changes in wall tension, both acutely and over time. We conclude that the primary stimulus for altered TM expression in vein grafts is the exposure to arterial pressure. Furthermore, these data identify strain as a novel and important pathway for in vivo TM gene regulation.

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Immunolocalization and temporal distribution of cytokine expression during the development of vein graft intimal hyperplasia in an experimental model

Cited by 56 publications

References 24 publications

Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2

Matrix metalloproteinase expression in vein grafts: role of inflammatory mediators and extracellular signal-regulated kinases-1 and -2

Graft-Extrinsic Cells Predominate in Vein Graft Arterialization

Wall Tension Is a Potent Negative Regulator of In Vivo Thrombomodulin Expression

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