The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment

Kilari, Sreenivasulu; Cai, Chuanqi; Zhao, Chunrong; Sharma, Amit; Chernogubova, Ekaterina; Simeon, Michael L.; Wu, Chin Cheng; Song, Hsiang‐Lin; Maegdefessel, Lars; Misra, Sanjay

doi:10.1016/j.ymthe.2019.06.011

Cited by 22 publications

(15 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is consistent with previous study in murine AVFs using 1,25 NP 7 . Several studies have demonstrated that reduced FSP-1 staining is associated with improved vascular remodeling in experimental AVFs 20 . Moreover, there was no difference in FAP-1 staining indicating 1,25 NP treatment had no effect on fibroblast activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

Cai

Kilari

Zhao

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D3, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C–C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-μL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson’s trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The endothelial cells were isolated from each patient’s sample and analyzed for gene expression of Ier3 using quantitative real time polymerase chain reaction (qRT-PCR) as described previously 20 . At day 3, 1,25 NP or vehicle treated murine outflow veins were analyzed for gene expression of Ier3 and Ccl2 .…”

Section: Methodsmentioning

confidence: 99%

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

Cai

Kilari

Zhao

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Male C57BL/6J mice weighing 19 -25 g were obtained from Jackson Laboratories (Bar Harbor, ME) and housed at 22°C, 41% relative humidity, and 12:12-h light-dark cycles. CKD was induced by performing a 5/6 renal nephrectomy, as previously described (13).…”

Section: Methodsmentioning

confidence: 99%

Increased fibrotic signaling in a murine model for intra-arterial contrast-induced acute kidney injury

Sharma

Kilari

Cai

et al. 2020

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 μL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated ( P < 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-β1, TGF-β receptor type I, and TGF-β receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and −9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration ( P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-β1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-β1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.

show abstract

“…Studies with female mice are warranted because female sex is an important variable that predicts reduced maturation in human AVF. 50 Additional clarification of the effects of TGF-β inhibition on AVF remodeling could also determine other cell type–specific TGF-β disruption, such as in fibroblasts or leukocytes, as these cells are essential during AVF remodeling 21,51 ; these transgenic mice were not available at the time of this study.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency

Taniguchi

Ohashi

Lee

et al. 2022

ATVB

View full text Add to dashboard Cite

BACKGROUND: Arteriovenous fistulae (AVF) are the gold standard for vascular access for hemodialysis. Although the vein must thicken and dilate for successful hemodialysis, excessive wall thickness leads to stenosis causing AVF failure. Since TGF-β (transforming growth factor-beta) regulates ECM (extracellular matrix) deposition and smooth muscle cell (SMC) proliferation—critical components of wall thickness—we hypothesized that disruption of TGF-β signaling prevents excessive wall thickening during venous remodeling. METHODS: A mouse aortocaval fistula model was used. SB431542—an inhibitor of TGF-β receptor I—was encapsulated in nanoparticles and applied to the AVF adventitia in C57BL/6J mice. Alternatively, AVFs were created in mice with conditional disruption of TGF-β receptors in either SMCs or endothelial cells. Doppler ultrasound was performed serially to confirm patency and to measure vessel diameters. AVFs were harvested at predetermined time points for histological and immunofluorescence analyses. RESULTS: Inhibition of TGF-β signaling with SB431542-containing nanoparticles significantly reduced p-Smad2–positive cells in the AVF wall during the early maturation phase (days 7–21) and was associated with decreased AVF wall thickness that showed both decreased collagen density and decreased SMC proliferation. SMC-specific TGF-β signaling disruption decreased collagen density but not SMC proliferation or wall thickness. Endothelial cell–specific TGF-β signaling disruption decreased both collagen density and SMC proliferation in the AVF wall and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. CONCLUSIONS: Endothelial cell–targeted TGF-β inhibition may be a translational strategy to improve AVF patency.

show abstract

The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment

Cited by 22 publications

References 26 publications

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D3 attenuates restenosis in a murine angioplasty model

Increased fibrotic signaling in a murine model for intra-arterial contrast-induced acute kidney injury

Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency

Contact Info

Product

Resources

About