Adventitial remodeling with increased matrix metalloproteinase-2 activity in a porcine arteriovenous polytetrafluoroethylene grafts

Misra, Sanjay; Doherty, Michael; Woodrum, David A.; Homburger, Jay; Mandrekar, Jayawant; Elkouri, Stéphane; Sabater, Enrique A.; Bjarnason, Haraldur; Fu, Alex A.; Glockner, James F.; Greene, Eddie L.; Mukhopadhyay, Debabrata

doi:10.1111/j.1523-1755.2005.00763.x

Cited by 67 publications

(124 citation statements)

References 25 publications

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“…Experiments using animal models of hemodialysis vascular access failure have been used to identify the potential origin of cells contributing to the formation of the neointima. In 2005, in a porcine AVG model, Misra and colleagues demonstrated that the origin of the early cells causing venous stenosis formation after AVG placement resided in the adventitia and media (42). These results were corroborated by Cheung and colleagues, who showed in a porcine AVG model that adventitial fibroblasts begin to differentiate into myofibroblasts and contribute to neointimal cells (43).…”

Section: Origins Of Neointimal Cells In Vascular Access Dysfunctionsupporting

confidence: 72%

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

Lee

Misra

2016

CJASN

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Vascular access dysfunction remains a major cause of morbidity and mortality in hemodialysis patients. At present there are few effective therapies for this clinical problem. The poor understanding of the pathobiology that leads to arteriovenous fistula (AVF) and graft (AVG) dysfunction remains a critical barrier to development of novel and effective therapies. However, in recent years we have made substantial progress in our understanding of the mechanisms of vascular access dysfunction. This article presents recent advances and new insights into the pathobiology of AVF and AVG dysfunction and highlights potential therapeutic targets to improve vascular access outcomes.

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Section: Origins Of Neointimal Cells In Vascular Access Dysfunctionsupporting

confidence: 72%

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

Lee

Misra

2016

CJASN

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“…This contention is based on the observations that an imbalance of MMP activity over TIMPs promotes the migration and proliferation of smooth muscle cells (2,21) and that certain MMPs increase the bioavailability of VEGF-A, potentially accelerating the development of intimal hyperplasia (30). Previous work from our laboratory also supports a prominent role for MMPs in hemodialysis graft failure; we reported that PTFE grafts in pigs exhibited early upregulation of MMP-2 associated with increased cell migration from the adventitia to the media and intima and the subsequent formation of venous stenosis (35). Furthermore, nonspecific MMP-2 and MMP-9 inhibitors reduced the formation of neointima in the same model (49).…”

mentioning

confidence: 49%

“…Another group of cytokines that are thought to play a key role in hemodialysis graft failure and remodeling of vein grafts used as arterial conduits are matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs) (6,35,36,38,49). This contention is based on the observations that an imbalance of MMP activity over TIMPs promotes the migration and proliferation of smooth muscle cells (2,21) and that certain MMPs increase the bioavailability of VEGF-A, potentially accelerating the development of intimal hyperplasia (30).…”

mentioning

confidence: 99%

Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts

Misra¹,

Fu²,

Puggioni³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Venous injury and subsequent venous stenosis formation are responsible for hemodialysis graft failure. Our hypothesis is that these pathological changes are in part related to changes in wall shear stress (WSS) that results in the activation of matrix regulatory proteins causing subsequent venous stenosis formation. In the present study, we examined the serial changes in WSS, blood flow, and luminal vessel area that occur subsequent to the placement of a hemodialysis graft in a porcine model of chronic renal insufficiency. We then determined the corresponding histological, morphometric, and kinetic changes of several matrix regulatory proteins including VEGF-A, its receptors, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2. WSS was estimated by obtaining blood flow and luminal vessel area by performing phase-contrast MRI with magnetic resonance angiography in 21 animals at 1 day after graft placement and prior to death on day 3 ( n = 7), day 7 ( n = 7), and day 14 ( n = 7). At all time points, the mean WSS at the vein-to-graft anastomosis was significantly higher than that at the control vein ( P < 0.05). WSS had a bimodal distribution with peaks on days 1 and 7 followed by a significant reduction in WSS by day 14 ( P < 0.05 compared with day 7) and a decrease in luminal vessel area compared with control vessels. By day 3, there was a significant increase in VEGF-A and pro-MMP-9 followed by, on day 7, increased pro-MMP-2, active MMP-2, and VEGF receptor (VEGFR)-2 ( P < 0.05) and, by day 14, increased VEGFR-1 and TIMP-1 ( P < 0.05) at the vein-to-graft anastomosis compared with control vessels. Over time, the neointima thickened and was composed primarily of α-smooth muscle actin-positive cells with increased cellular proliferation. Our data suggest that hemodialysis graft placement leads to early increases in WSS, VEGF-A, and pro-MMP-9 followed by subsequent increases in pro-MMP-2, active MMP-2, VEGFR-1, VEGFR-2, and TIMP-1, which may contribute to the development of venous stenosis.

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“…In our case, the timed inhibition of c-Kit in adventitial and neointimal cells from day 0 to day 7 in rats effectively diminished the accumulation of cells in the neointima of newly created fistulae, suggesting a role for this receptor in the differentiation and/or mobilization of myofibroblasts within the vascular wall. Adventitial fibroblasts/myofibroblasts are believed to be one of the main sources of neointimal cells in the A-V fistula wall (33). However, the mechanisms by which c-Kit signaling modifies vein remodeling and determines NIH require further investigation.…”

Section: Discussionmentioning

confidence: 99%

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Skartsis

Martinez

Duque

et al. 2014

American Journal of Physiology-Renal Physiology

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Skartsis N, Martinez L, Duque JC, Tabbara M, Velazquez OC, Asif A, Andreopoulos F, Salman LH, Vazquez-Padron RI. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae. Am J Physiol Renal Physiol 307: F1095-F1104, 2014. First published September 3, 2014 doi:10.1152/ajprenal.00292.2014.-Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-Kit W/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. arteriovenous fistula; hemodialysis; neointima THE ARTERIOVENOUS (A-V) fistula is the preferred type of vascular access for hemodialysis patients (29). It achieves higher patency rates, has fewer complications than synthetic grafts (12,29,31), and has a lower risk of infections than central venous catheters (17,29). Despite its advantages, A-V fistulae frequently fail to mature or become dysfunctional after successful dialysis sessions, and this occurs primarily due to the development of neointimal hyperplasia (NIH) within the A-V fistula circuit (2, 5, 39). Stenosed A-V fistulae can sometimes be salvaged through angioplasty or surgical interventions, but these attempts often result in restenosis or additional complications (32). Therefore, there is an unmet medical need for treatments that prevent NIH and improve A-V fistula function. To this end, it is necessary to better define the factors underlying the pathological remodeling of the A-V fistula wall.A-V fistula maturation is a dynamic vascular process with multiple factors contributing to the development of NIH. These include vein configuration (22) In the present study, we investigated the role of c-Kit in the pathological remodeling of A-V fistulae. We show that activation of the c-Kit signaling pathway in adventitial and neointimal cells precedes arteri...

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Adventitial remodeling with increased matrix metalloproteinase-2 activity in a porcine arteriovenous polytetrafluoroethylene grafts

Cited by 67 publications

References 25 publications

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

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