Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency

Guo, Xiaojia; Fereydooni, Arash; Isaji, Toshihiko; Gorecka, Jolanta; Liu, Shirley; Hu, Haidi; Ono, Shun; Alozie, Michelle; Lee, Shin Rong; Taniguchi, Rin Ichiro; Yatsula, Bogdan; Nassiri, Naiem; Zhang, Lan; Dardik, Alan

doi:10.1038/s41598-019-47542-5

Cited by 31 publications

(29 citation statements)

References 43 publications

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“…We have previously shown that Akt1 knockout mice have reduced wall thickness after AVF creation, 16 and inhibition of the Akt1-mTORC1 axis with rapamycin resulted in thinner remodeled veins. 61 Thus, the increased outward remodeling and wall thickening that occurs during venous remodeling after activation of EphrinB2 signaling may be mediated via enhanced eNOS, Akt1, and hoc; 0 versus 5 min); P [ 0.001 (post hoc; 0 versus 15 min). n MAPK signaling; although we have previously shown the importance of the eNOS 21 and Akt1 61 pathways for venous remodeling, these pathways are not specific to EphrinB2 signaling.…”

Section: Discussionmentioning

confidence: 99%

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Wang

Liu

et al. 2021

Journal of Surgical Research

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Background: Arteriovenous fistulae (AVF) are the preferred mode of vascular access for hemodialysis. Before use, AVF remodel by thickening and dilating to achieve a functional conduit via an adaptive process characterized by expression of molecular markers characteristic of both venous and arterial identity. Although signaling via EphB4, a determinant of venous identity, mediates AVF maturation, the role of its counterpart EphrinB2, a determinant of arterial identity, remains unclear. We hypothesize that EphrinB2 signaling is active during AVF maturation and may be a mechanism of venous remodeling. Methods: Aortocaval fistulae were created or sham laparotomy was performed in C57Bl/6 mice, and specimens were examined on Days 7 or 21. EphrinB2 reverse signaling was activated with EphB4-Fc applied periadventitially in vivo and in endothelial cell culture medium in vitro. Downstream signaling was assessed using immunoblotting and immunofluorescence. Results: Venous remodeling during AVF maturation was characterized by increased expression of EphrinB2 as well as Akt1, extracellular signal-regulated kinases 1/2 (ERK1/ 2), and p38. Activation of EphrinB2 with EphB4-Fc increased phosphorylation of Eph-rinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and was associated with increased diameter and wall thickness in the AVF. Both mouse and human endothelial cells treated with EphB4-Fc increased phosphorylation of EphrinB2, endothelial nitric oxide synthase, Akt1, ERK1/2, and p38 and increased endothelial cell tube formation and migration. Conclusions: Activation of EphrinB2 signaling by EphB4-Fc was associated with adaptive venous remodeling in vivo while activating endothelial cell function in vitro.

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Section: Discussionmentioning

confidence: 99%

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Wang

Liu

et al. 2021

Journal of Surgical Research

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“…Consistent with previous studies, the diameter of the IVC distal to the AVF site in mice with an AVF but without a stenosis also increased compared with the IVC diameter of sham-operated mice ( Fig 2, B and D ; blue vs black), both upstream and downstream of the stenosis. 8 , 10 , 17 , 18 Mice with both a stenosis and an AVF also showed a large upstream IVC diameter and smaller IVC downstream diameter, compared with mice with an AVF but without a stenosis ( Fig 2, B and D ; red vs blue). In mice with an IVC stenosis alone, the IVC diameter was similar to sham-operated mice, both upstream and downstream of the stenosis ( Fig 2, B and D ; green vs black).…”

Section: Resultsmentioning

confidence: 93%

A mouse model of stenosis distal to an arteriovenous fistula recapitulates human central venous stenosis

Taniguchi

Ono

Isaji

et al. 2020

JVS-Vascular Science

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Objective: Central venous stenosis (CVS) is a major cause of arteriovenous fistula (AVF) failure. However, central veins are relatively inaccessible to study with conventional Doppler ultrasound methods. To understand mechanisms underlying AVF failure owing to CVS, an animal model was established that creates a stenosis distal to an AVF. We hypothesized that this mouse model will show comparable morphology and physiology to human CVS. Methods: An aortocaval fistula was created between the distal aorta and inferior vena cava (IVC); a stenosis was then created distal to the fistula by partial IVC ligation. Sham-operated animals, AVF without venous stenosis, and venous stenosis without AVF were used as controls. Physiologic properties of the IVC, both upstream and downstream of the stenosis, or the corresponding sites in models without stenosis, were assessed with ultrasound examination on days 0 to 21. The spectral broadening index was measured to assess the degree of disturbed shear stress. The IVC was harvested at day 21 and specimens were analyzed with immunofluorescence. Results: The IVC diameter of mice with an AVF and stenosis showed increased upstream ( P = .013), but decreased downstream diameter ( P = .001) compared with mice with an AVF but without a stenosis, at all postoperative times (days 3–21). IVC wall thickness increased in mice with an AVF, compared with IVC without an AVF (upstream of stenosis: 13.9 μm vs 11.0 μm vs 4.5 μm vs 3.9 μm; P = .020; downstream of stenosis: 6.0 μm vs 6.6 μm vs μm 4.5 μm vs 3.8 μm; P = .002; AVF with stenosis, AVF, stenosis, sham, respectively). AVF patency significantly decreased in mice with an AVF and stenosis by day 21 (50% vs 90%; P = .048). The IVC of mice with AVF and stenosis showed a venous waveform with pulsatility as well as enhanced velocity at and downstream of the stenosis; similar waveforms were observed in a human case of CVS. Downstream to the stenosis, the spectral broadening index was significantly higher compared with mice with AVF alone (1.06 vs 0.78; P = .011; day 21), and there was a trend towards less immunoreactivity of both Krüppel-like factor 2 and phosphorylated-endothelial nitric oxide synthase compared with mice with an AVF alone. Conclusions: Partial IVC ligation distal to a mouse aortocaval fistula alters the fistula diameter and wall thickness, decreases patency, and increases distal disturbed flow compared with fistulae without a distal stenosis. Our mouse model of stenosis distal to an AVF may be a faithful representation of human CVS that shows similar morphology and physiology, including disturbed shear stress.

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“…In the current AV fistula model, CD44 was elevated after AV fistula creation in WT mice, and the surge was attenuated in MMP-9 −/− mice (WT CTL 0.16 ± 0.06 vs. WT AVF 0.81 ± 0.11, MMP-9 −/− CTL 0.18 ± 0.09 vs. 0.43 ± 0.04; p < 0.0001 and p = 0.0123, respectively; n = 6 in each group; Figure 7 B). In addition to CD44, the Akt and ERK phosphorylation is also linked to AV fistula stenosis [ 12 , 39 ]. Phospho-Akt was significantly upregulated after AV fistula surgery and MMP-9 deficiency ameliorated the effect (WT CTL 1.32 ± 0.26 vs. WT AVF 2.72 ± 0.26, MMP-9 −/− CTL 0.59 ± 0.06 vs. MMP-9 −/− 1.36 ± 0.17; p = 0.0006 and 0.0009 respectively; Figure 7 C).…”

Section: Resultsmentioning

confidence: 99%

MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation

Shih

Chen

et al. 2021

IJMS

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Matrix metalloproteinase 9 (MMP-9) expression is upregulated in vascular inflammation and participates in vascular remodeling, including aneurysm dilatation and arterial neointima development. Neointima at the arteriovenous (AV) fistula anastomosis site primarily causes AV fistula stenosis and failure; however, the effects of MMP-9 on perioperative AV fistula remodeling remain unknown. Therefore, we created AV fistulas (end-to-side anastomosis) in wild-type (WT) and MMP-9 knockout mice with chronic kidney disease to further clarify this. Neointima progressively developed in the AV fistula venous segment of WT mice during the four-week postoperative course, and MMP-9 knockout increased the lumen area and attenuated neointima size by reducing smooth muscle cell and collagen components. Early perioperative AV fistula mRNA sequencing data revealed that inflammation-related gene sets were negatively enriched in AV fistula of MMP-9 knockout mice compared to that in WT mice. qPCR results also showed that inflammatory genes, including tumor necrosis factor-a (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), were downregulated. In addition, Western blot results showed that MMP-9 knockout reduced CD44 and RAC-alpha serine/threonine-protein kinase (Akt) and extracellular signal-regulated kinases (ERK) phosphorylation. In vitro, MMP-9 addition enhanced IL-6 and MCP-1 expression in vascular smooth muscle cells, as well as cell migration, which was reversed by an MMP-9 inhibitor. In conclusion, MMP-9 knockout attenuated AV fistula stenosis by reducing perioperative vascular inflammation.

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Inhibition of the Akt1-mTORC1 Axis Alters Venous Remodeling to Improve Arteriovenous Fistula Patency

Cited by 31 publications

References 43 publications

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

Activation of EphrinB2 Signaling Promotes Adaptive Venous Remodeling in Murine Arteriovenous Fistulae

A mouse model of stenosis distal to an arteriovenous fistula recapitulates human central venous stenosis

MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation

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