Expression of Hypoxia Inducible Factor–1α, Macrophage Migration Inhibition Factor, Matrix Metalloproteinase–2 and −9, and Their Inhibitors in Hemodialysis Grafts and Arteriovenous Fistulas

Misra, Sanjay; Fu, Alex A.; Rajan, Dheeraj K.; Juncos, Luis A.; McKusick, Michael A.; Bjarnason, Haraldur; Mukhopadhyay, Debabrata

doi:10.1016/j.jvir.2007.10.031

Cited by 67 publications

(83 citation statements)

References 20 publications

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“…Substantial evidence indicates that MMP-9 exerts vasculopathic effects that include the marked stimulation of proliferation and migration of smooth muscle cells and proinflammatory effects (6,9,46); upregulation of MMP-9 is implicated in the promotion of neotimal hyperplasia in the injured vasculature and assorted vasculopathies that include dysfunction of hemodialysis vascular accesses (6,7,8,9,10,20,25,29,33,46). We thus examined expression of MMP-9 and HO-1 in the AVF in HO-2 ϩ/ϩ and HO-2 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Functioning of an arteriovenous fistula requires heme oxygenase-2

Grande

Farrugia

et al. 2013

American Journal of Physiology-Renal Physiology

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Heme oxygenase-2 (HO-2), the constitutive isoform of the heme-degrading enzyme heme oxygenase, may serve as an anti-inflammatory vasorelaxant, in part, by generating carbon monoxide. Arteriovenous fistulas (AVFs) are employed as hemodialysis vascular accesses because they provide an accessible, high-blood-flow vascular segment. We examined the role of vascular expression of HO-2 in AVF function. An AVF was created in mice by anastomosing the carotid artery to the jugular vein. HO-2 expression was detected by immunohistochemistry in the intact carotid artery, mainly in endothelial cells and smooth muscle cells; expression of HO-2 protein and mRNA was modestly increased in the artery of the AVF. Creating an AVF in HO-2(-/-) mice compared with an AVF in HO-2(+/+) mice led to markedly reduced AVF blood flow and increased numbers of nonfunctioning AVFs. The impairment of AVF function in the setting of HO-2 deficiency could not be ascribed to either preexisting intrinsic abnormalities in endothelium-dependent and endothelium-independent relaxation of the carotid artery in HO-2-deficient mice or to impaired vasorelaxant responses in the intact carotid artery in vivo. HO-1 mRNA was comparably induced in the AVF in HO-2(+/+) and HO-2(-/-) mice, whereas the AVF in HO-2(-/-) mice compared with that in HO-2(+/+) mice exhibited exaggerated induction of matrix metalloproteinase (MMP)-9 but similar induction of MMP-2. HO-2 deficiency also led to lower AVF blood flow when AVFs were created in uremia, the latter induced by subtotal nephrectomy. We conclude that HO-2 critically contributes to the adequacy of AVF blood flow and function.

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Section: Discussionmentioning

confidence: 99%

Functioning of an arteriovenous fistula requires heme oxygenase-2

Grande

Farrugia

et al. 2013

American Journal of Physiology-Renal Physiology

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“…The role of MAPK is supported by the observation that the increase in HIF mRNA expression and the reduction in IVC contraction associated with prolonged vein wall stretch are reversed in veins treated with MAPK inhibitors (Lim et al, 2011). Additional evidence supporting the role of HIFs as factors linking increased venous pressure and MMP expression in VVs is that HIF-1a and -2a transcription factors and HIF target genes are upregulated in VVs (Lim et al, 2012), and that the expression and activity of MMP-2 and -9 can be regulated by HIF-1a in hemodialysis grafts and arteriovenous fistulas (Misra et al, 2008). In addition to mechanical stretch, low oxygen tension, hormones, cytokines, heat, and low pH may also induce HIF expression and, in turn, increase MMP levels.…”

Section: Hypoxia and Mmps In Vvsmentioning

confidence: 94%

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

MacColl

Khalil

2015

J Pharmacol Exp Ther

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Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward the heart against hydrostatic venous pressure. Matrix metalloproteinases (MMPs) play an important role in maintaining vein wall structure and function. MMPs are zinc-binding endopeptidases secreted as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. ProMMPs are activated by various activators including other MMPs and proteinases. MMPs cause degradation of extracellular matrix (ECM) proteins such as collagen and elastin, and could have additional effects on the endothelium, as well as VSM cell migration, proliferation, Ca 21 signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/ activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP expression/activity, ECM degradation, VSM relaxation, and venous dilation. Leukocyte infiltration and inflammation of the vein wall cause further increases in MMPs, vein wall dilation, valve degradation, and different clinical stages of chronic venous disease (CVD), including varicose veins (VVs). VVs are characterized by ECM imbalance, incompetent valves, venous reflux, wall dilation, and tortuosity. VVs often show increased MMP levels, but may show no change or decreased levels, depending on the VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.

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“…Both patients receiving AVGs and porcine AVG models have increased levels of hypoxia-inducible factor 1-α (HIF-1α) expression in locations of restenosis [92, 93]. In stenotic vein samples obtained from 6 AVG patients upon graft failure, a large range of protein factors associated with HIF-1α were upregulated within 6 cm of the graft-venous anastomosis, including HIF-1α itself (1.8-fold vs. control vein), macrophage migration inhibition factor (8.6-fold), MMP-2 (2.8-fold) and MMP-9 (2.5-fold), and tissue inhibitor of MMPs-1 (TIMP-1) (8.9-fold) [93].…”

Section: Endothelial Cell Responses To Physiological and Arteriovenoumentioning

confidence: 99%

“…In stenotic vein samples obtained from 6 AVG patients upon graft failure, a large range of protein factors associated with HIF-1α were upregulated within 6 cm of the graft-venous anastomosis, including HIF-1α itself (1.8-fold vs. control vein), macrophage migration inhibition factor (8.6-fold), MMP-2 (2.8-fold) and MMP-9 (2.5-fold), and tissue inhibitor of MMPs-1 (TIMP-1) (8.9-fold) [93]. In a porcine model of AVG, many of these factors were increased in both the vein and also artery adjoining the graft, including MMP-2 and -9 [94, 95], and TIMP-1 and -2 [94].…”

Section: Endothelial Cell Responses To Physiological and Arteriovenoumentioning

confidence: 99%

Hemodynamic Shear Stress and Endothelial Dysfunction in Hemodialysis Access

Fitts¹,

Pike²,

Anderson³

et al. 2014

TOUNJ

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Surgically-created blood conduits used for chronic hemodialysis, including native arteriovenous fistulas (AVFs) and synthetic AV grafts (AVGs), are the lifeline for kidney failure patients. Unfortunately, each has its own limitations: AVFs often fail to mature to become useful for dialysis and AVGs often fail due to stenosis as a result of neointimal hyperplasia, which preferentially forms at the graft-venous anastomosis. No clinical therapies are currently available to significantly promote AVF maturation or prevent neointimal hyperplasia in AVGs. Central to devising strategies to solve these problems is a complete mechanistic understanding of the pathophysiological processes. The pathology of arteriovenous access problems is likely multi-factorial. This review focuses on the roles of fluid-wall shear stress (WSS) and endothelial cells (ECs). In arteriovenous access, shunting of arterial blood flow directly into the vein drastically alters the hemodynamics in the vein. These hemodynamic changes are likely major contributors to non-maturation of an AVF vein and/or formation of neointimal hyperplasia at the venous anastomosis of an AVG. ECs separate blood from other vascular wall cells and also influence the phenotype of these other cells. In arteriovenous access, the responses of ECs to aberrant WSS may subsequently lead to AVF non-maturation and/or AVG stenosis. This review provides an overview of the methods for characterizing blood flow and calculating WSS in arteriovenous access and discusses EC responses to arteriovenous hemodynamics. This review also discusses the role of WSS in the pathology of arteriovenous access, as well as confounding factors that modulate the impact of WSS.

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Expression of Hypoxia Inducible Factor–1α, Macrophage Migration Inhibition Factor, Matrix Metalloproteinase–2 and −9, and Their Inhibitors in Hemodialysis Grafts and Arteriovenous Fistulas

Cited by 67 publications

References 20 publications

Functioning of an arteriovenous fistula requires heme oxygenase-2

Functioning of an arteriovenous fistula requires heme oxygenase-2

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Hemodynamic Shear Stress and Endothelial Dysfunction in Hemodialysis Access

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