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Objective To observe the effects of photodynamic therapy (PDT) with hematoporphyrin monomethyl ether (HMME) on venous neointimal hyperplasia (VNH) in arteriovenous fistulas (AVFs) in rabbits. Methods We established models of AVF by end-to-side anastomosis of the common carotid artery to the jugular vein in 32 adult rabbits, which were randomized into 4 groups (n=8), including a control group without any intervention, an HMME group with HMME treatment only, a light illumination (without HMME) group, and a HMME-PDT group receiving both the photosensitizer and light illumination. Color Doppler ultrasound was used to detect the blood flow after the operation. At 30 d after the operation, the jugular vein tissue was collected for assessing VNH and measurement of the lumen area using HE and Masson staining and for detecting the expression of proliferating cell nuclear antigen (PCNA) and ɑ-smooth muscle actin (ɑ-SMA) using immunohistochemistry; Western blotting was performed to analyze the expression of proliferating cell nuclear antigen (PCNA), Bcl-2, ɑ-SMA, Caspase3, Caspase9 and Bax. Results The jugular vein tissues showed significantly lessened VNH and increased lumen area in HMME-PDT group compared with the other groups (P < 0.05). The results of immunohistochemistry showed that the expression of PCNA and ɑ-SMA was decreased and Caspase3 expression was increased significantly in HMME-PDT group compared with the other groups (P < 0.05). Western blotting results showed that among the 4 groups, the expression of Caspase3, Caspase9 and Bax were the highest (P < 0.05) while those of PCNA, Bcl-2, ɑ-SMA and Bcl-2/Bax ratio the lowest in HMME-PDT group (P < 0.05). Conclusion HMME-PDT can effectively reduce VNH in AVFs in rabbits by suppressing proliferation and promoting apoptosis of the vascular smooth muscle cells via the Bcl-2/Bax pathway.

Arteriovenous fistula (AVF) failure often involves venous neointimal hyperplasia (VNH) driven by elevated hypoxia-inducible factor-1 alpha (HIF-1α) in the venous wall. Omentin, known for its anti-inflammatory and anti-hyperplasia properties, has an uncertain role in early AVF failure. This study investigates omentin's impact on VNH using a chronic renal failure (CRF) rabbit model. The CRF rabbit model of AVF received omentin-expressing adenoviral vector or control β-gal vector to assess omentin's effects on VNH. Human vascular smooth muscle cells (HVSMCs), stimulated with tumor necrosis factor-α (TNF-α), were exposed to recombinant human omentin (Rh-OMT) to study its influence on cell proliferation and migration. The AMP-activated protein kinase (AMPK) inhibitor compound C and the mammalian target of rapamycin (mTOR) activator MHY1485 were employed to explore omentin's mechanisms in VNH reduction through HIF-1α inhibition. Omentin treatment reduced VNH in CRF rabbits, concomitant with HIF-1α down-regulation and the suppression of downstream factors, including vascular endothelial growth factor and matrix metalloproteinases. Rh-OMT inhibited TNF-α-induced HVSMC proliferation and migration by modulating both cell cycle and cell adhesion proteins. Additionally, omentin reduced HIF-1α expression through the AMPK/mTOR pathway activation. Notably, the blockade of AMPK/mTOR signaling reversed omentin-mediated inhibition of VNH, cell proliferation, and migration, both in vivo and in vitro. In conclusion, omentin mitigates VNH post-AVF creation by restraining HIF-1α via AMPK/mTOR signaling. Strategies boosting circulating omentin levels may offer promise in averting AVF failure. • Omentin reduces AVF neointimal thickening and cellular proliferation. • HIF-1α suppression enhances AVF maturation. • Omentin inhibits neointima via AMPK/mTOR/HIF-1α pathway. [ABSTRACT FROM AUTHOR]

Background: To investigate the technical advantages of a modified no-touch technique (MNTT) in constructing arteriovenous fistulas (AVF) compared to the conventional technique (CT) and assess its potential to reduce neointimal hyperplasia in the outflow vein., Methods: Forty-seven New Zealand rabbits were randomly divided into three groups: control, CT, and MNTT. Rabbits in control group were observed using ultrasound and then euthanized to obtain external jugular vein (EJV) for Hematoxylin-eosin (H-E). We established common carotid artery (CCA)-EJV AVF using MNTT in the MNTT group and the CT in the CT group. AVF patency and complications were compared between the CT and MNTT groups. Rabbits with patent AVF in both groups were observed using ultrasound 2 weeks after surgery to evaluate changes in the vessel diameter and blood flow spectrum of the AVFs. H-E staining measured the intima thickness of EJV adjacent to the anastomosis and histologic characteristics of the AVF at 2 and 4 weeks after surgery., Results: Five rabbits died after surgery with common symptoms of sneezing, coughing, runny nose, anorexia, and diarrhea; two in the MNTT group and three in the CT group. There were significant differences in the diameter ( p  = 0.010) and peak systolic velocities (PSV) ( p  = 0.001) of EJV between the CT and MNTT groups 2 weeks after surgery. Spiral laminar flow (SLF) was observed in CCA and EJV adjacent to anastomosis in the MNTT group. Additionally, histological observations showed less venous neointimal hyperplasia in the MNTT group than in the CT group 4 weeks after surgery., Conclusion: The rabbit model of CCA-EJV AVF established using MNTT demonstrated fewer com p lications, larger vein diameters, and reduced venous neointimal hyperplasia, indicating that this maybe an ideal animal model to further investigate the application of MNTT in AVF surgery., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex‐specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real‐time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b), with increased transforming growth factor‐β1 (Tgf‐β1) and transforming growth factor‐β receptor 1 (Tgfβ‐r1). There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf‐β1, Tgfβ‐r1, and Col1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf‐β1 and Tgfβ‐r1, and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.

One of the main problems related to inadequate planning of vascular access is dysfunction during maturation. Arteriovenous fistula dysfunction is most often a consequence of neointimal hyperplasia. Important causes for initial dysfunction of the fistula include narrow lumens of the arteries and veins used for anastomosis, damage to the vascular endothelium during fistula creation, previous venipuncture, postoperative development of venous collaterals, the impact force of friction on the arteriovenous anastomosis, a genetic predisposition for development of vascular stenosis, neointimal hyperplasia and previously persistent venous neointimal hyperplasia. Any damage to the endothelium is a stimulus for neointimal hyperplasia. During surgery for creating the fistula, endothelial cells separate on the intima, edema appears, fibrin is deposited, leukocytes and platelets infiltrate. Spotted edema and necrosis of smooth muscle cells appear in the media. In order to determine an adequate therapeutic strategy, the pathogenesis of intimal hyperplasia has been widely considered from different aspects. It is currently based on preoperative preservation of veins and careful selection of blood vessels, percutaneous transluminal angioplasty or surgical revision. Nevertheless, no current therapeutic strategies provide appropriate recommendations to improve maturation of the arteriovenous fistula. Notwithstanding considerable knowledge about the pathogenesis of venous neointimal hyperplasia, currently no prophylactic treatments would reduce its progression.

Aim An arteriovenous fistulae ( AVF) is the preferred vascular access for maintenance haemodialysis patients. Its dysfunction is often due to venous stenosis, which is mainly caused by neointimal hyperplasia. Additionally, haemodynamic forces, especially wall shear stress ( WSS), as a mechanical stimuli to venous wall have a significant role in neointimal hyperplasia. The purpose of this study was to evaluate the association between WSS and neointimal hyperplasia. Methods An 'end-to-side' AVF was created between the right femoral artery and vein of canines. Canines were killed at 7 and 28 days post-surgery. The velocity and WSS in the three-dimensional computational model of AVF were simulated using computational fluid dynamics ( CFDs). The four typical sites of the vein evaluated in this study, chosen according to the haemodynamic analysis, included the arteriovenous anastomosis ( A-V), the juxta-anastomotic segment ( J-V), the juxta-ligation segment ( L-V) and the proximal vein ( P-V). The specimens were haematoxylin-eosin stained and the intima-media thickening was then measured. Results Neointimal hyperplasia was more obvious in the inner wall of the J-V and L-V (low-and-disturbed WSS) sites compared with the P-V and A-V sites, and the outer wall of the L-V and J-V segments (high or laminar WSS) ( P < 0.01). Conclusion In this study, we described the haemodynamic condition in the AVF and found that neointimal hyperplasia predisposed to occur in the inner wall of venous segment near the anastomosis. We also found that not only the neointimal hyperplasia has a strong inverse correlation with WSS levels, but also is related to flow patterns. [ABSTRACT FROM AUTHOR]

Background. Venous neointimal hyperplasia is the most common cause of arteriovenous (AV) fistula and graft dysfunction following dialysis access surgery. However, the pathogenetic impact of pre-existing venous neointimal hyperplasia at the time of AV access creation on final clinical success is currently unknown in the setting of advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The aim of this study was to perform a detailed histological, morphometric, and immunohistochemical analysis of vein specimens in advanced CKD and ESRD patients collected at the time of new vascular access placement.Methods. Vein samples from 12 patients were collected at the time of AV access creation near the site of AV anastomosis. Histological, immunohistochemistry and morphometric studies were performed on these vein samples.Results. Examination of the tissue specimens obtained at the time of surgery showed neointimal hyperplasia in 10 of 12 specimens, ranging from minimal to very severe. The majority of cells within the neointima were myofibroblasts with a minority of contractile smooth muscle cells present.Conclusion. Our work represents a detailed description of the morphometric and cellular phenotypic lesions present in the veins of CKD and ESRD patients, prior to dialysis access placement. These studies (i) suggest the future possibility of a new predictive marker (pre-existing venous neointimal hyperplasia) for AV dialysis access dysfunction and (ii) open the door for the future development of novel local therapies for optimization of the venous substrate on which the dialysis access is created. [ABSTRACT FROM AUTHOR]

Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is a leading cause of hospitalization and morbidity. The aim of the current study was to identify the specific cell types present within stenotic tissue samples from patients with AV fistula and graft failure. [ABSTRACT FROM PUBLISHER]

Purpose: Hemodialysis vascular access dysfunction is an enormous clinical problem that causes great morbidity and costs well over one billion dollars per annum. The vast majority of hemodialysis vascular access dysfunction occurs as a result of venous stenosis and thrombosis at the graft-vein anastomosis. At a cellular level, this venous stenosis is the result of venous neointimal hyperplasia (VNH). There are, unfortunately, no effective therapies for VNH. The purpose of this study was to assess the role of external radiation therapy in preventing VNH and venous stenosis.Methods and Materials: Seven-centimeter polytetrafluoroethylene loop grafts were placed bilaterally between the femoral artery and vein of 12 Yorkshire Cross pigs. One side was treated with a single 16-Gy dose of external beam radiation with a linear accelerator, while the contralateral side served as an internal control. Swine were killed after 28 days, and the grafts were carefully dissected out and removed. Neointimal hyperplasia and luminal stenosis were then assessed morphometrically at the graft-vessel anastomoses.Results: External beam radiation therapy significantly reduced the amount of luminal stenosis at the graft-vein anastomosis, with minimal local and systemic toxicity.Conclusions: External beam radiation therapy could be a useful and clinically relevant local treatment for venous stenosis in polytetrafluoroethylene dialysis grafts. [Copyright &y& Elsevier]

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex-specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real-time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b) , with increased transforming growth factor-β1 ( Tgf-β1) and transforming growth factor-β receptor 1 ( Tgfβ-r1) . There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf-β1 , Tgfβ-r1 , and Col1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf-β1 and Tgfβ-r1 , and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.

Objective: To invesitigate 3-year patency rate of autogenous arteriovenous fistula(AVF)in the patients with late fistula dysfunction/failure. Methods: The prospective study was carried out in the First Hospital of Tsinghua University from March 2012 to March 2013. A total of 136 maintenance hemodialysis patients with late AVF dysfunction/faliure who received AVF repairment were enrolled in the study. All the patients were divided into three groups according to surgical procedures: venous neointimal hyperplasia (VNH) stripping group (group A), non-VNH stripping group (group B) and creation of a new AVF group (group C). Patency rate was calculated by survival analysis method, and survival curve of fistula was drawn as well. Results: During 12-36 months follow-up, there were 46 patients with late AVF dysfunction/faliure in group A, 38 patients in group B, and 52 pateints in group C. The AVF patency rate was 88.6% at 12th month, 77.6% at 24th month, and 57.2% at 36th month in group A; 89.3% at 12th month, 74.5% at 24th month, and 55.1% at 36th month in group B; 88.1% at 12th month, 76.8% at 24th month, and 59.0% at 36th month in group C. The AVF patency rates had no statistical difference among three groups at three time points (12th, 24th and 36th month) ( P >0.05). Conclusion: The patency rate was high in the patients who recieved AVF repairment. There was no significant difference in the patency rate among three different surgical treatments.

Pericardial patches are commonly used during cardiovascular surgery to close blood vessels. In arteries, patches accumulate arterial progenitor cells; we hypothesized that venous patches would accumulate venous progenitor cells, in the absence of arterial pressure. We developed a novel rat inferior vena cava (IVC) venotomy model and repaired it with a pericardial patch. Cells infiltrated the patch to form a thick neointima by day 7; some cells were CD34(+)/VEGFR2(+) and CD31(+)/Eph-B4(+) consistent with development of venous identity in the healing patch. Compared to arterial patches, the venous patches had increased neointimal thickness at day 7 without any pseudoaneurysms. Addition of an arteriovenous fistula (AVF) to increase blood flow on the patch resulted in reduced patch neointimal thickness and proliferation, but neointimal thickness was not reversible with AVF ligation. These results show that rat patch venoplasty is a novel model of aggressive venous neointimal hyperplasia., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The arteriovenous fistula has been used for more than 50 years to provide vascular access for patients undergoing hemodialysis. More than 1.5 million patients worldwide have end stage renal disease and this population will continue to grow. The arteriovenous fistula is the preferred vascular access for patients, but its patency rate at 1 year is only 60%. The majority of arteriovenous fistulas fail because of intimal hyperplasia. In recent years, there have been many studies investigating the molecular mechanisms responsible for intimal hyperplasia and subsequent thrombosis. These studies have identified common pathways including inflammation, uremia, hypoxia, sheer stress, and increased thrombogenicity. These cellular mechanisms lead to increased proliferation, migration, and eventually stenosis. These pathways work synergistically through shared molecular messengers. In this review, we will examine the literature concerning the molecular basis of hemodialysis vascular access malfunction., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)