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Kadsura heteroclita (Roxb) Craib also named Xuetong in Tujia ethnomedicine in China, has been traditionally employed in rheumatoid arthritis (RA) treatment. Our preceding investigations have elucidated that Xuetongsu (XTS), a triterpenoid compound predominant in Xuetong, showed excellent anti-RA-fibroblast-like synoviocytes (RAFLS) proliferation effect. However, XTS belongs to the trace components of the Xuetong plant, which poses certain limitations to the research. In this study, we designed a method that enhanced the extraction yield of XTS and explored the mechanism of its inhibition of RAFLS cell proliferation and migration in the treatment of RA. The results displayed that XTS reduced RAFLS cell proliferation, with an IC 50 value of 4.68 ± 0.65 µM. A series of experimental techniques were utilized to show that XTS induce apoptosis in RAFLS cells at concentrations ranging from 4.5 to 18 µM, including wound healing assay, flow cytometry, and western blot analysis. Moreover, XTS at dosages of 0.42-0.84 mg/kg markedly attenuated paw swelling and synovial hyperplasia in arthritic rats, primarily through the inhibition of RAFLS migration and promotion of RAFLS apoptosis via High mobility group box 1 (HMGB-1)/Matrix metalloproteinase-9 (MMP-9)/MMP-13 signaling pathway and Bcl-2/Bax/Caspase-3 signaling pathway, respectively., (© 2024. The Author(s).)

Peripheral artery disease is commonly treated with balloon angioplasty, a procedure involving minimally invasive, transluminal insertion of a catheter to the site of stenosis, where a balloon is inflated to open the blockage, restoring blood flow. However, peripheral angioplasty has a high rate of restenosis, limiting long-term patency. Therefore, angioplasty is sometimes paired with delivery of cytotoxic drugs like paclitaxel to reduce neointimal tissue formation. We pursue intravascular drug delivery strategies that target the underlying cause of restenosis - intimal hyperplasia resulting from stress-induced vascular smooth muscle cell switching from the healthy contractile into a pathological synthetic phenotype. We have established MAPKAP kinase 2 (MK2) as a driver of this phenotype switch and seek to establish convective and contact transfer (coated balloon) methods for MK2 inhibitory peptide delivery to sites of angioplasty. Using a flow loop bioreactor, we showed MK2 inhibition in ex vivo arteries suppresses smooth muscle cell phenotype switching while preserving vessel contractility. A rat carotid artery balloon injury model demonstrated inhibition of intimal hyperplasia following MK2i coated balloon treatment in vivo. These studies establish both convective and drug coated balloon strategies as promising approaches for intravascular delivery of MK2 inhibitory formulations to improve efficacy of balloon angioplasty., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Our objective was to explore the safety and efficacy of a graphene oxide-loaded rapamycin-coated self-expandable metallic airway stent (GO@RAPA-SEMS) in a rabbit model., Methods: The dip coating method was used to develop a GO@RAPA-SEMS and a poly(lactic-co-glycolic)-acid loaded rapamycin-coated self-expandable metallic airway stent (PLGA@RAPA-SEMS). The surface structure was evaluated using a scanning electronic microscope. The in vitro drug-release profiles of the 2 stents were explored and compared. In the animal study, a total of 45 rabbits were randomly divided into 3 groups and underwent 3 kinds of stent placements. Computed tomography was performed to evaluate the degree of stenosis at 1, 2 and 3 months after the stent operation. Five rabbits in each group were sacrificed after the computed tomography scan. The stented trachea and blood were collected for further pathological analysis and laboratory testing., Results: The in vitro drug-release study revealed that GO@RAPA-SEMS exhibited a sudden release on the first day and maintained a certain release rate on the 14th day. The PLGA@RAPA-SEMS exhibited a longer sustained release time. All 45 rabbits underwent successful stent placement. Pathological results indicated that the granulation tissue thickness in the GO@RAPA-SEMS group was less than that in the PLGA@RAPA-SEMS group. The TUNEL and hypoxia-inducible factor-1α staining results support the fact that the granulation inhibition effect in the GO@RAPA-SEMS group was greater than that in the PLGA@RAPA-SEMS group., Conclusions: GO@RAPA-SEMS effectively inhibited stent-related granulation tissue hyperplasia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Restenosis frequently occurs after percutaneous angioplasty in patients with vascular occlusion and seriously threatens their health. Substantial evidence has revealed that preventing vascular smooth muscle cell proliferation using a drug-eluting stent is an effective approach to improve restenosis. Cucurbitacins have been demonstrated to exert an anti-proliferation effect in various tumors and a hypotensive effect. This study aims to investigate the role of cucurbitacins extracted from Cucumis melo L. (CuECs) and cucurbitacin B (CuB) on restenosis., Methods: C57BL/6 mice were subjected to left carotid artery ligation and subcutaneously injected with CuECs or CuB for 4 weeks. Hematoxylin-Eosin, immunofluorescence and immunohistochemistry staining were used to evaluate the effect of CuECs and CuB on neointimal hyperplasia. Western blot, real-time PCR, flow cytometry analysis, EdU staining and cellular immunofluorescence assay were employed to measure the effects of CuECs and CuB on cell proliferation and the cell cycle in vitro. The potential interactions of CuECs with cyclin A2 were performed by molecular docking., Results: The results demonstrated that both CuECs and CuB exhibited significant inhibitory effects on neointimal hyperplasia and proliferation of vascular smooth muscle cells. Furthermore, CuECs and CuB mediated cell cycle arrest at the S phase. Autodocking analysis demonstrated that CuB, CuD, CuE and CuI had high binding energy for cyclin A2. Our study also showed that CuECs and CuB dramatically inhibited FBS-induced cyclin A2 expression. Moreover, the expression of cyclin A2 in CuEC- and CuB-treated neointima was downregulated., Conclusions: CuECs, especially CuB, exert an anti-proliferation effect in VSMCs and may be potential drugs to prevent restenosis., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: Intimal hyperplasia is a normal adaptive feature of arteries in response to injuries, which include invasive vascular interventions. Its development limits the long-term success of bypass grafts. Various pharmacological agents have been successfully employed in experimental models to reduce the degree of intimal hyperplasia. In our study, we investigated the efficacy of dexamethasone in reducing intimal hyperplasia in rat abdominal aortas after partial transection and primary repair., Methods: In this study, 20 Wistar Albino rats were randomly selected and divided into four groups to compare the effects of low- and high-dose dexamethasone on intima and media thickness compared to the control. Group A (n=5) was the control group, where only skin incision and laparotomy were performed. For Group B (n=5), a median laparotomy was performed, the abdominal aorta was partially transected, and repaired with an 8.0 prolene suture. Doses of 0.1 mg/kg and 0.2 mg/kg dexamethasone were administered in Group C (n=5) and Group D (n=5), respectively. After two weeks, all rats were euthanized, and the repaired abdominal aortas were excised and examined histopathologically. Intima and media thicknesses were measured using the 'Olympus AnalySIS 5' program (Olympus Corporation, Japan) after digital photos were taken., Results: Based on the measurements, we demonstrated that after transection and repair of the abdominal aorta, the intima/media ratio was not significantly different between the low-dose dexamethasone and non-dexamethasone groups. The intima/media ratio was significantly lower in the high-dose dexamethasone group than in the non-dexamethasone and low-dose dexamethasone groups., Conclusion: After vascular interventions, dexamethasone treatment may reduce intimal hyperplasia and increase patency by providing vascular remodeling.

Despite the significant progress made in recent years, clinical issues with small-diameter vascular grafts related to low mechanical strength, thrombosis, intimal hyperplasia, and insufficient endothelialization remain unresolved. This study aims to design and fabricate a core-shell fibrous small-diameter vascular graft by co-axial electrospinning process, which will mechanically and biologically meet the benchmarks for blood vessel replacement. The presented graft (PGHV) comprised polycaprolactone/gelatin (shell) loaded with heparin-VEGF and polycaprolactone (core). This study hypothesized that the shell structure of the fibers would allow rapid degradation to release heparin-VEGF, and the core would provide mechanical strength for long-term application. Physico-mechanical evaluation, in vitro biocompatibility, and hemocompatibility assays were performed to ensure safe in vivo applications. After 25 days, the PGHV group released 79.47 ± 1.54% of heparin and 86.25 ± 1.19% of VEGF, and degradation of the shell was observed but the core remained pristine. Both the control (PG) and PGHV groups demonstrated robust mechanical properties. The PGHV group showed excellent biocompatibility and hemocompatibility compared to the PG group. After four months of rat aorta implantation, PGHV exhibited smooth muscle cell regeneration and complete endothelialization with a patency rate of 100%. The novel core-shell structured graft could be pivotal in vascular tissue regeneration application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Effective therapies for the prevention of vein graft failure, which frequently occurs in coronary artery bypass grafting (CABG) due to intimal hyperplasia (IH), are still lacking. Here, we investigated the effects of the perivenous application of double-network hydrogel on vein grafts in carotid artery bypass grafting in a rabbit model., Methods: Healthy New Zealand white rabbits were randomized into the following groups: no graft, graft, or graft + Double-network hydrogel external stent (DNHES). The rabbits' carotid artery was bypassed via the jugular vein. Double-network hydrogel external stent was wrapped around the jugular graft after the anastomoses were completed. Blood flow parameters and tissue histology of the vein grafts were evaluated., Results: Compared with the untreated vein grafts at 12 weeks after the surgery, the DNHES significantly improved graft flow, attenuated intimal and medial thickening, reduced the anti-proliferating cell nuclear antigen proliferation index of the vein grafts, decreased the mRNA and protein expression of Mitogen-Activated Protein Kinase (MAPK) and Transforming Growth Factor-β (TGF-β), and increased the mRNA and protein expression of endothelial Nitric Oxide Synthase (eNOS)., Conclusion: The perivenous application of DNHES exerts beneficial effects on vein grafts, reduces the inflammatory response in carotid artery bypass grafting in a rabbit model, and appears to be a safe and promising strategy to prevent vein graft failure.

We previously showed decellularized fish swim bladder can be used as vascular patch and tube graft in rats, mesenchymal stem cells (MSCs) have showed the capability to inhibit neointimal hyperplasia in different animal models. We hypothesized that decellularized fish swim bladder patch loaded with MSCs (bioinspired patch) can inhibit neointimal hyperplasia in a rat aortic patch angioplasty model. Rat MSCs were grown in vitro and flow cytometry was used to confirm their quality. 3.6 × 10 5 MSCs were mixed into 100 μl of sodium alginate (SA)/hyaluronic acid (HA) hydrogel, two layers of fish swim bladders (5 mm × 5 mm) were sutured together, bioinspired patch was created by injection of hydrogel with MSCs into the space between two layers of fish swim bladder patches. Decellularized rat thoracic aorta patch was used as control. Patches were harvested at days 1 and 14 after implantation. Samples were examined by histology, immunohistochemistry, and immunofluorescence. The decellularized rat thoracic aorta patch and the fish swim bladder patch had a similar healing process after implantation. The bioinspired patch had a similar structure like native aorta. Bioinspired patch showed a decreased neointimal thickness (p = .0053), fewer macrophages infiltration (p = .0090), and lower proliferation rate (p = .0291) compared to the double layers fish swim bladder patch group. Decellularized fish swim bladder patch loaded with MSCs can inhibit neointimal hyperplasia effectively. Although this is a preliminary animal study, it may have a potential application in large animals or clinical research., (© 2022 Wiley Periodicals LLC.)

Post-operative complications of vascular anastomosis procedures remain a significant clinical challenge and health burden globally. Each year, millions of anastomosis procedures connect arteries and/or veins in vascular bypass, vascular access, organ transplant, and reconstructive surgeries, generally via suturing. Dysfunction of these anastomoses, primarily due to neointimal hyperplasia and the resulting narrowing of the vessel lumen, results in failure rates of up to 50% and billions of dollars in costs to the healthcare system. Non-absorbable sutures are the gold standard for vessel anastomosis; however, damage from the surgical procedure and closure itself causes an inflammatory cascade that leads to neointimal hyperplasia at the anastomosis site. Here, we demonstrate the development of a novel, scalable manufacturing system for fabrication of high strength sutures with nanofiber-based coatings composed of generally regarded as safe (GRAS) polymers and either sirolimus, tacrolimus, everolimus, or pimecrolimus. These sutures provided sufficient tensile strength for maintenance of the vascular anastomosis and sustained drug delivery at the site of the anastomosis. Tacrolimus-eluting sutures provided a significant reduction in neointimal hyperplasia in rats over a period of 14 days with similar vessel endothelialization in comparison to conventional nylon sutures. In contrast, systemically delivered tacrolimus caused significant weight loss and mortality due to toxicity. Thus, drug-eluting sutures provide a promising platform to improve the outcomes of vascular interventions without modifying the clinical workflow and without the risks associated with systemic drug delivery., Competing Interests: Declaration of Competing Interest KSP, JH, and LE have filed patent applications regarding the subject matter of this manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The association between inflammatory bowel disease and colorectal cancer is well known. Although the overall incidence of inflammatory bowel disease has declined recently, patients with this disease still have a 1.7-fold increased risk of colorectal cancer. The risk factors for developing colorectal cancer include extensive colitis, young age at diagnosis, disease duration, primary sclerosing cholangitis, chronic colonic mucosal inflammation, dysplasia lesion, and post-inflammatory polyps. In patients with inflammatory bowel disease, control of chronic inflammation and surveillance colonoscopies are important for the prevention of colorectal cancer. The 2017 guidelines from the European Crohn's and Colitis Organisation suggest that colonoscopies to screen for colorectal cancer should be performed when inflammatory bowel disease symptoms have lasted for 8 years. Current evidence supports the use of chemoprevention therapy with mesalamine to reduce the risk of colorectal cancer in patients with ulcerative colitis. Other compounds, including thiopurine, folic acid, statin, and tumor necrosis factor-α inhibitor, are controversial. Large surveillance cohort studies with longer follow-up duration are needed to evaluate the impact of drugs on colorectal cancer risks.

Background: Colorectal cancer is related to ulcerative colitis. This study aimed to investigate the effects of aspirin on non-specific inflammation developing into cancer., Methods: Ulcerative colitis model was generated by administrating azoxymethane/dextran sulfate sodium to mice. Weight, tumor size/ amount, and intestinal mucositis scores were analyzed. Inflammatory cell infiltration and atypical hyperplasia were determined with hematoxylin-eosin staining. Immunohistochemical assay was used to detect the proliferating cell nuclear antigen. Interleukin-6 and interleukin-10 were detected using enzyme-linked immunosorbent assay. Signal transducer and activator of transcription 3, phosphorylated-STAT3, cyclin D1, and suppressor of cytokine signaling 3 were examined with western blotting., Results: Aspirin remarkably decreased tumor size/amount compared to those of the ulcerative colitis model group (P < .05). Interleukin-6 was increased and interleukin-10 was decreased in mice of ulcerative colitis model group compared with the control group (P < .05). Aspirin markedly reduced interleukin-6 and enhanced interleukin-10 compared to the ulcerative colitis model group (P < .05) induced Azoxymethane/dextran sulfate sodium inflammation (3 weeks) and atypical hyperplasia (8 weeks). Aspirin predominantly inhibited the "inflammation-atypical hyperplasia-cancer" process and alleviated inflammatory cell infiltration of mice in the ulcerative colitis model group. Aspirin promoted apoptosis and alleviated proliferating cell nuclear antigen of atypical hyperplastic intestinal mucosal cells at 8 weeks post-modeling. The expression of phosphorylated-STAT3, signal transducer and activator of transcription 3, cyclin D1, and suppressor of cytokine signaling 3 was significantly increased in mice of ulcerative colitis model group compared to the control group (P < .05). Aspirin remarkably decreased phosphorylated-STAT3, signal transducer and activator of transcription, and cyclin D1 expression compared with ulcerative colitis model group (P < .05)., Conclusion: Aspirin inhibited carcinogenesis of intestinal mucosal cells in the ulcerative colitis model by inhibiting the interleukin-6/ Janus kinase/signal transducer and activator of transcription 3 signaling pathway and promoted apoptosis, thereby suppressing proliferation.

Intimal hyperplasia (IH) occurs in a considerable number of cases of blood vessel reconstruction by stenting or balloon angioplasty, venous bypass grafting, and arteriovenous dialysis accesses. It is triggered by endothelial injury during the vascular intervention and leads to vessel restenosis with life-threatening consequences for patients. To date, the drugs used for IH prevention in clinics-paclitaxel and rapalog drugs-have been focusing primarily on the vascular smooth muscle cell (VSMC) proliferation pathway of IH development. Limitations, such as endothelial toxicity and inappropriate drug administration timing, have spurred the search for new and efficient pharmacological approaches to control IH. In this state-of-the-art review, we present the pathways of IH development, focusing on the key events and actors involved in IH. Subsequently, we discuss different drugs and drug combinations interfering with these pathways based on their effect on peripheral circulation IH models in animal studies, or on clinical reports. The reports were obtained through an extensive search of peer-reviewed publications in Pubmed, Embase, and Google Scholar, with search equations composed based on five concepts around IH and their various combinations. To improve vascular intervention outcomes, rethinking of conventional therapeutic approaches to IH prevention is needed. Exploring local application of drugs and drug combinations acting on different pathophysiological pathways of IH development has the potential to provide effective and safe restenosis prevention., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Drug-coated balloons (DCBs) offer potential to deliver drugs to treat coronary lesions but without leaving permanent implants behind. Paclitaxel and sirolimus are anti-proliferation drugs that are commonly used in commercially available DCBs. However, these drugs present significant cytotoxicity concern and low efficacy in vivo . Here, we use microRNA-22 (miR-22) as balloon loaded drugs and polyelectrolyte complexes (PECs) polyethyleneimine/polyacrylic acid (PEI/PAA) as balloon coatings to establish a new DCB system through the ultrasonic spray method. The PEI/PAA forms a stable and thin coating on the balloon, which resulted in a good transfer capacity to the vessel wall both in vitro and in vivo . miR-22 that could modulate smooth muscle cell (SMC) phenotype switching is incorporated into the PEI/PAA coating and shows a sustained release profile. The PEI/PAA/miR-22 coated balloon successfully inhibits intima hyperplasia after balloon-induced vascular injury in a rat model through decreasing proliferative SMCs via the miR-22-methyl-CpG binding protein 2 (MECP2) axis. Our findings indicate that balloons coated with PEI/PAA/miR-22 have great potential to be promising DCBs in the treatment of cardiovascular disease.

Purpose: An arteriovenous fistula (AVF) is the preferred vascular access mode for maintenance hemodialysis, and access stenosis and thrombosis are the primary causes of AVF dysfunction. This study is aimed at exploring the molecular mechanisms underlying AVF development and the roles of the heme oxygenase 1/peroxisome proliferator-activated receptor gamma (HO-1/PPAR- γ ) pathway in AVF., Method: AVF model mice were established, and the vascular tissues from the arteriovenous anastomosis site were sent for mRNA sequencing. Differentially expressed mRNAs (DEmRNAs) were screened and subjected to functional analysis. Thereafter, the mice with HO-1 knockdown and coprotoporphyrin IX chloride (COPP) pretreatment were used to investigate the roles of the HO-1/PPAR- γ pathway in AVF., Results: By sequencing, 2514 DEmRNAs, including 1323 upregulated and 1191 downregulated genes, were identified. These DEmRNAs were significantly enriched in the PPAR signaling pathway, AMPK signaling pathway, glucagon signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway. High expression of HO-1 and PPAR- γ reduced endothelial damage and intimal hyperplasia during AVF maturation. After AVF was established, the levels of transforming growth factor- β (TGF- β ), interleukin-1 β (IL-1 β ), interleukin-18 (IL-18), and reactive oxygen species (ROS) were significantly increased ( P < 0.05), and HO-1 normal expression and COPP pretreatment evidently decreased their levels in AVF ( P < 0.05). Additionally, AVF significantly upregulated HO-1 and PPAR- γ and downregulated MMP9, and COPP pretreatment and HO-1 normal expression further upregulated and downregulated their expression., Conclusion: The HO-1/PPAR- γ pathway may suppress intimal hyperplasia induced by AVF and protect the intima of blood vessels by regulating MMP9 and ROS, thus mitigating AVF dysfunction., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Tingfei Xie et al.)

Various preclinical studies with developed Eustachian tube (ET) stents are in progress but have not yet been clinically applied. ET stent is limited by stent-induced tissue hyperplasia in preclinical studies. The effectiveness of sirolimus-eluting cobalt-chrome alloy stent (SES) in suppressing stent-induced tissue hyperplasia after stent placement in the porcine ET model was investigated. Six pigs were divided into two groups (i.e., the control and the SES groups) with three pigs for each group. The control group received an uncoated cobalt-chrome alloy stent (n = 6), and the SES group received a sirolimus-eluting cobalt-chrome alloy stent (n = 6). All groups were sacrificed 4 weeks after stent placement. Stent placement was successful in all ETs without procedure-related complications. None of the stents was able to keep its round shape as original, and mucus accumulation was observed inside and around the stent in both groups. On histologic analysis, the tissue hyperplasia area and the thickness of submucosal fibrosis were significantly lower in the SES group than in the control group. SES seems to be effective in suppressing stent-induced tissue hyperplasia in porcine ET. However, further investigation was required to verify the optimal stent materials and antiproliferative drugs., (© 2022. The Author(s).)

Objectives: Intima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model., Methods: Donor rat aortic grafts (n = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml-1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n = 12) received DCA via drinking water during the whole follow-up period (0.75 g l-1), while rats without DCA treatment served as controls (n = 10). At 2 (n = 6 + 5) and 8 (n = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence., Results: Systemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51-1.27] vs 1.49 [0.67-2.39] without DCA, P < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0-0.25] vs 0.63 [0.06-1.44] without DCA, P < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative., Conclusions: Systemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Lack of long-term patency has hindered the clinical use of small-diameter prosthetic vascular grafts with the majority of these failures due to the development of neointimal hyperplasia. Previous studies by our laboratory revealed that small-diameter expanded polytetrafluoroethylene (ePTFE) grafts coated with antioxidant elastomers are a promising localized therapy to inhibit neointimal hyperplasia. This work is focused on the development of poly(diol-co-citrate-co-ascorbate) (POCA) elastomers with tunable properties for coating ePTFE vascular grafts. A bioactive POCA elastomer (@20 : 20 : 8, [citrate] : [diol] : [ascorbate]) coating was applied on a 1.5 mm diameter ePTFE vascular graft as the most promising therapeutic candidate for reducing neointimal hyperplasia. Surface ascorbate density on the POCA elastomer was increased to 67.5 ± 7.3 ng mg -1 cm -2 . The mechanical, antioxidant, biodegradable, and biocompatible properties of POCA demonstrated desirable performance for in vivo use, inhibiting human aortic smooth muscle cell proliferation, while supporting human aortic endothelial cells. POCA elastomer coating number was adjusted by a modified spin-coating method to prepare small-diameter ePTFE vascular grafts similar to natural vessels. A significant reduction in neointimal hyperplasia was observed after implanting POCA-coated ePTFE vascular grafts in a guinea pig aortic interposition bypass graft model. POCA elastomer thus offers a new avenue that shows promise for use in vascular engineering to improve long-term patency rates by coating small-diameter ePTFE vascular grafts.

Scars are often considered to be skin problems that affect beauty. The tension acting on the edge of the wound is the main factor causing the scar hyperplasia. At present, the clinical use of botulinum toxin A (BTX-A) around the wound to cause transient muscle paralysis reduce the muscle movement around the wound and wound tension to prevent scar hyperplasia during wound healing. But the use of BTX-A to prevent scarring requires the use of a syringe. The syringe can cause trauma and pain when it pricks the skin for BTX-A injection. The conotoxin which is secreted by the poison glands on the inside of the venom tube and capsule of the snail provides a simple and effective way to prevent skin scar hyperplasia. We reviewed the classification of conotoxin, the conotoxin's mechanism of preventing scar hyperplasia, and the research direction of conotoxin in the future and provided reference for promoting the application of conotoxin in preventing skin scar hyperplasia., (© 2020 Wiley Periodicals LLC.)

Colon cancer is the commonest cancer worldwide. α-Hederin is a monodesmosidic triterpenoid saponin possessing diverse pharmacological activities. The running experiment was designed to test the chemopreventive activity of α-hederin when used as an adjuvant to carboplatin in an experimental model of mouse colon hyperplasia induced by 1,2-dimethylhydrazine (DMH). Fifty male Swiss albino mice were classified into five groups: group (I): saline group, group (II): DMH-induced colon hyperplasia control group, group (III): DMH + carboplatin (5 mg/kg) group, group (IV): DMH + α-hederin (80 mg/kg) group, and group (V): DMH + carboplatin (5 mg/kg)+α-hederin (80 mg/kg) group. Analyzing of colonic tissue indicated that the disease control group showed higher colon levels of phospho-PI3K to total-PI3K, phospho-AKT to total-AKT and cyclin D1 concurrent with lower phospho-JNK/total JNK ratio and caspase 3. However, treatment with α-hederin, in combination with carboplatin, favorably ameliorated phosphorylation of PI3K/AKT/JNK proteins, increased colon caspase 3 and downregulated cyclin D1. Microscopically, α-hederin, in combination with carboplatin, produced the most reduction in the histologic hyperplasia score, enhanced the goblet cell survival in periodic acid Schiff staining and reduced proliferation (Ki-67 immunostaining) in the current colon hyperplasia model. Collectively, the current study highlighted for the first time that using α-hederin as an adjuvant to carboplatin enhanced its chemopreventive activity, improved JNK signaling and increased apoptosis. Hence, further studies are warranted to test α-hederin as a promising candidate with chemotherapeutic agents in treating colon cancer.

Vascular dysfunction in cardiovascular diseases includes vasomotor response impairments, endothelial cells (ECs) activation, and smooth muscle cells (SMCs) proliferation and migration to the intima. This results in intimal hyperplasia and vessel failure. We previously reported that activation of the P2Y11 receptor (P2Y11R) in human dendritic cells, cardiofibroblasts and cardiomyocytes was protective against hypoxia/reoxygenation (HR) lesions. In this study, we investigated the role of P2Y11R signaling in vascular dysfunction. P2Y11R activity was modulated using its pharmacological agonist NF546 and antagonist NF340. Rat aortic rings were exposed to angiotensin II (AngII) and evaluated for their vasomotor response. The P2Y11R agonist NF546 reduced AngII-induced vascular dysfunction by promoting EC-dependent vasorelaxation, through an increased nitric oxide (NO) bioavailability and reduced AngII-induced H 2 O 2 release; these effects were prevented by the use of the P2Y11R antagonist NF340. Human vascular SMCs and ECs were subjected to AngII or H/R simulation in vitro. P2Y11R agonist modulated vasoactive factors in human ECs, that is, endothelial nitric oxide synthase (eNOS) and endothelin-1, reduced SMC proliferation and prevented the switch towards a synthetic phenotype. H/R and AngII increased ECs secretome-induced SMC proliferation, an effect prevented by P2Y11R activation. Thus, our data suggest that P2Y11R activation may protect blood vessels from HR-/AngII-induced injury and reduce vascular dysfunctions. These results open the way for new vasculoprotective interventions.

Mutations in BRCA genes are the leading cause of hereditary breast cancer. Current options to prevent cancer in these high-risk patients, such as anti-estrogen drugs and radical mastectomy, are limited by lack of efficacy, undesirable toxicities, or physical and emotional challenges. We have previously shown that PARP inhibitors can significantly delay tumor development in BRCA1-deficient mice. Here, we fabricated the PARP inhibitor talazoparib (TLZ) into spacer implants (InCeT-TLZ) for localized and sustained delivery. We hypothesized that this novel formulation will provide an effective chemopreventive strategy with minimal toxicity. TLZ was released gradually over 30 days as implants degraded. InCeT-TLZ significantly decreased proliferation and increased DNA damage in the mammary glands of BRCA1-deficient mice. Notably, the number of mice that developed hyperplasia in the mammary glands was significantly lower with InCeT-TLZ treatment compared to the control group. Meanwhile, InCeT-TLZ was also better tolerated than oral TLZ, without loss of body weight or anemia. This study provides proof of concept for a novel and safe chemopreventive strategy using localized delivery of a PARP inhibitor for high-risk individuals. Future studies will directly evaluate the effects of InCeT-TLZ for preventing tumor development.

Stent-related granulation tissue hyperplasia is a major complication that limits the application of stents in airways. In this study, an arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent (ATO-NFCS) was developed. Poly-L-lactide-caprolactone (PLCL) was selected as the drug-carrying polymer. Stents with two different ATO contents (0.4% ATO/PLCL and 1.2% ATO/PLCL) were fabricated. The in vitro release in simulated airway fluid suggested that the total ATO release time was 1 d. The growth of human embryonic pulmonary fibroblasts (CCC-HPF-1), normal human bronchial epithelial cells and airway smooth muscle cells was inhibited by ATO. When embedded in paravertebral muscle, the nanofiber membrane showed good short-term and long-term biological effects. In an animal study, placement of the ATO-NFCS in the trachea through a delivery system under fluoroscopy was feasible. The changes in liver and kidney function 1 and 7 d after ATO-NFCS placement were within the normal range. On pathological examination, the heart, liver, spleen, lungs and kidneys were normal. The effectiveness of the ATO-NFCS in reducing granulation tissue hyperplasia and collagen deposition was demonstrated in the rabbit airway (n = 18) at 4 weeks. The present study preliminarily investigated the efficacy of the ATO-NFCS in reducing granulation tissue formation in the trachea of rabbits. The results suggest that the ATO-NFCS is safe in vivo, easy to place, and effective for the suppression of granulation tissue formation.

Background Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end-stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP-SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease. Methods and Results Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 μL of PBS or 20 μL of PBS with 16.6 mg/mL of either MP or MP-SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase-polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor-A ( Vegf-A ), matrix metalloproteinase-9 ( Mmp-9 ), transforming growth factor beta 1 ( Tgf-β1 ), and monocyte chemoattractant protein-1 ( Mcp-1 ) were significantly decreased in MP-SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP-SV treated outflow veins. MP-SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of Vegf-A and Mmp-9 . Conclusions In experimental arteriovenous fistulas, periadventitial delivery of MP-SV decreased gene expression of Vegf-A , Mmp-9 , Tgf-β1 and Mcp-1, VNH/VS, inflammation, and fibrosis.

Excessive proliferation, migration and dedifferentiation of vascular smooth muscle cells (VSMCs) are the center of intimal formation during in-stent restenosis and vein graft disease. Paeoniflorin-6'-O-benzene sulfonate (CP-25) is known to suppress inflammation and atherogenesis. However, the potential effect of CP-25 on intimal formation remains elusive. In the present study, we found that CP-25 significantly attenuated wire injury-induced intimal formation in C57BL/6 mice (intimal area: 2.64 ± 0.25 × 10 4  μm 2 vs. 1.53 ± 0.21 × 10 4  μm 2 , P < 0.05) and vascular hyperplasia indicated by PCNA staining. In vitro experiments showed that CP-25 significantly alleviated human aortic smooth muscle cell (HASMC) proliferation, migration and dedifferentiation induced by PDGF-BB. Mechanistically, CP-25 inhibited GRK2 phosphorylation through PDGF receptor in the presence of PDGF-BB. In accordance with these results, CP-25 disrupted the interaction of GRK2 with ERK1/2 and suppressed the activation of ERK1/2 signaling in HASMCs. EVI1, which is considered as a downstream of ERK1/2 signaling and a novel transcription factor for VSMC differentiation, was also downregulated by CP-25 treatment. Moreover, overexpression of EVI1 partly restored the decreased proliferation and dedifferentiation of HASMCs treated by CP-25. Collectively, these findings suggested that CP-25 could alleviate intimal formation in response to wire injury via suppression of the interaction of GRK2 and ERK1/2 and EVI1 activation, indicating CP-25 might serve as a potent pharmaceutical for intimal formation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Intracoronary stenting is a common procedure in patients with coronary artery disease (CAD). Stent deployment stretches and denudes the endothelial layer, promoting a local inflammatory response, resulting in neointimal hyperplasia. Vitamin D deficiency associates with CAD. In this study, we examined the association of vitamin D status with high mobility group box 1 (HMGB1)-mediated pathways (HMGB1, receptor for advanced glycation end products [RAGE], and Toll-like receptor-2 and -4 [TLR2 and TLR4]) in neointimal hyperplasia in atherosclerotic swine following bare metal stenting. Yucatan microswine fed with a high-cholesterol diet were stratified to receive vitamin D-deficient (VD-DEF), vitamin D-sufficient (VD-SUF), and vitamin D-supplemented (VD-SUP) diet. After 6 months, PTCA (percutaneous transluminal balloon angioplasty) followed by bare metal stent implantation was performed in the left anterior descending (LAD) artery of each swine. Four months following coronary intervention, angiogram and optical coherence tomography (OCT) were performed and swine euthanized. Histology and immunohistochemistry were performed in excised LAD to evaluate the expression of HMGB1, RAGE, TLR2, and TLR4. OCT analysis revealed the greatest in-stent restenosis area in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. The protein expression of HMGB1, RAGE, TLR2, and TLR4 was significantly higher in the LAD of VD-DEF compared to VD-SUF or VD-SUP swine. Vitamin D deficiency was associated with both increased in-stent restenosis and increased HMGB1-mediated inflammation noted in coronary arteries following intravascular stenting. Inversely, vitamin D supplementation was associated with both a decrease in this inflammatory profile and in neointimal hyperplasia, warranting further investigation for vitamin D as a potential adjunct therapy following coronary intervention.

Anti-atherogenic therapy is crucial in halting the progression of inflammation-induced intimal hyperplasia. The aim of this concise review was to methodically assess the recent findings of the different approaches, mainly on the recruitment of chemokines and/or cytokine and its effects in combating the intimal hyperplasia caused by various risk factors. Pubmed and Scopus databases were searched, followed by article selection based on pre-set inclusion and exclusion criteria. The combination of keywords used were monocyte chemoattractant protein-1 OR MCP-1 OR TNF-alpha OR TNF-α AND hyperplasia OR intimal hyperplasia OR neointimal hyperplasia AND in vitro. These keywords combination was incorporated in the study and had successfully identified 77 articles, with 22 articles were acquired from Pubmed, whereas 55 articles were obtained from Scopus. However, after title screening, only twelve articles meet the requirements of defined inclusion criteria. We classified the data into 4 different approaches, i.e., utilisation of natural product, genetic manipulation and protein inhibition, targeted drugs in clinical setting, and chemokine and cytokines induction. Most of the articles are working on genetic manipulation targeted on specific pathway to inhibit the pro-inflammatory factors expression. We also found that the utilisation of chemokine- and cytokine-related treatments are emerging throughout the years. However, there is no study utilising the combination of approaches that might give a better outcome in combating intimal hyperplasia. Hopefully, this concise review will provide an insight regarding the usage of different novel approaches in halting the progression of intimal hyperplasia, which serves as a key factor for the development of atherosclerosis in cardiovascular disease.

Coronary artery disease (CAD) is the most common cardiovascular disorder. Vascular surgery strategies for coronary revascularization (either percutaneous or open) show a high rate of failure because of restenosis of the vessel, due to phenotypic switch of vascular smooth muscle cells (VSMCs) leading to proliferation and migration. We have previously reported that the inhibition of Kv1.3 channel function with selective blockers represents an effective strategy for the prevention of restenosis in human vessels used for coronary angioplasty procedures. However, delivery systems for controlled release of these drugs have not been investigated. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models. The dose and time course of PAP-1 release from ELRs click hydrogels was able to inhibit human VSMC proliferation in vitro as well as remodeling of human vessels in organ culture and restenosis in in vivo models. We conclude that this combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients. STATEMENT OF SIGNIFICANCE: Vascular surgery strategies for coronary revascularization show a high rate of failure, because of occlusion (restenosis) of the vessel, due to vascular smooth muscle cells proliferation and migration. We have previously reported that blockers of Kv1.3 channels represent an effective anti-restenosis therapy, but delivery systems for their controlled release have not being explored. Here we tested the efficacy of several formulations of elastin like recombinamers (ELRs) hydrogels to deliver the Kv1.3 blocker PAP-1 in various restenosis models, both in vivo and in vitro, and also in human vessels. We demonstrated that combination of active compound and advanced delivery method could improve the outcomes of vascular surgery in patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The rate of saphenous vein graft failure one year after coronary artery bypass grafting ranges from 10% to 25%. The aim of this study was to explore whether atorvastatin can reduce accumulation of vascular smooth muscle cells to inhibit intimal hyperplasia via p38 MAPK pathway inhibition., Methods: Forty-five Sprague-Dawley rats were randomized to three groups. Thirty rats received a vein graft operation, and they were randomized to be treated with vehicle or atorvastatin; fifteen rats received a sham operation. We detected intimal hyperplasia by hematoxylin-eosin staining and related protein expression by immunohistochemical and Western blot analysis. Comparisons were analyzed by single-factor analysis of variance and Fisher's least significant difference test, with p < 0.05 considered significant., Results: The intima analyzed by hematoxylin-eosin staining was dramatically thicker in the control group than in the atorvastatin group and sham group (p < 0.01). The outcomes of immunohistochemical staining of α-SMA demonstrated that the percentage of α-SMA-positive cells in the control group was higher than in the atorvastatin group (p < 0.01). We also evaluated α-SMA, PCNA, p38 MAPK, and phosphorylation of p38 MAPK after statin treatment by Western blot analysis, and the results indicated that atorvastatin did not lead to p38 MAPK reduction (p < 0.05); it did, however, result in inhibition of p38 MAPK phosphorylation (p < 0.01), and it significantly reduced α-SMA and PCNA levels, in comparison with the control group (p < 0.01)., Conclusion: We have demonstrated that atorvastatin can inhibit accumulation of vascular smooth muscle cells by inhibiting the p38 MAPK pathway, and it is capable of inhibiting intimal hyperplasia in a rat vein graft model.

Objective: To investigate the anti-inflflammatory effects of Sanguisorbae Radix on contact dermatitis (CD)., Methods: Mice were sensitized by painting 30 µL of 1-fluoro-2,4-dinitrofluorobenzene (DNFB) onto each ear for 3 days. Four days later, mice were challenged by painting with 50 µL of DNFB onto the shaved dorsum every 2 days. Sanguisorbae Radix methanol extract (MESR) was applied onto the shaved dorsum every 2 days. The effects of MESR on skin thickness, skin weights, histopathological changes, skin lesions and cytokine production in DNFB-induced CD mice were investigated, as well as its effects on body weights and spleen/body weight ratio., Results: Topical application of MESR effectively inhibited enlargement of skin thickness and weight (P<0.05). MESR treatment also inhibited hyperplasia, spongiosis and immune cell infiltration induced by DNFB in inflamed tissues and improved lesions on dorsum skin in CD mice. Moreover, treatment with MESR suppressed the increase in the levels of tumor necrosis factor α (TNF-α,P<0.01) and interferon γ (IFN-γ,P<0.05), respectively. Finally, MESR had no effect on body weight gain or spleen/body weight ratio., Conclusion: These data suggest that MESR acts as an anti-inflflammatory agent that decreases the production of TNF-α and IFN-γ, resulting in reductions of skin lesions and histopathological changes in inflamed skin tissues.

Objectives: This study aims to extend the implantation lifetime of the puborectalis-like artificial anal sphincter by inhibiting the occurrence of hyperplasia following the implantation process., Method: A new transmission structure was designed inside the puborectalis-like artificial anal sphincter to generate an adequate torque to maintain the feces, even if hyperplasia developed around the prosthetic sphincter. An outer shell was added to the prosthetic sphincter to decelerate the occurrence of hyperplasia on the outer shell side. Medical titanium alloy was tested to replace the nylon-12 prosthetic sphincter, while polyetheretherketone was used for the construction of the power supply unit in the puborectalis-like artificial anal sphincter system instead of nylon-12. In vivo experiments were conducted to evaluate all the methods presented in this study with 10 Pa Ma piglets, 1 domestic pig, and 1 beagle dog during the past 2 years., Results: Compared with the previous prosthetic sphincter that was equipped with a fixed-axle gear transmission, the new transmission structure is equipped with a planet-gear train managed to generate a prosthetic sphincter output with a 53% larger torque but with the same size and type of motor as that used previously and increase the implantation lifetime by 56%. After the replacement of the nylon-12, the new prosthetic sphincter made of medical titanium alloy succeeded in extending the implanted lifetime by 83%. In addition, the lifetime was increased by 143%, when an outer shell was added to the prosthetic sphincter. Polyetheretherketone significantly decreased the growth rate of hyperplasia around the power supply unit by 44% after the replacement of the power supply unit material. After the combination of all the improvements, the longest implantation lifetime of the puborectalis-like artificial anal sphincter during the in vivo experiments was 7 months and 10 days, which reflected an improvement of 249%., Conclusion: All methods posted in this study were evaluated to be effective to prolong the implantation lifetime of the puborectalis-like artificial anal sphincter. Among the methods proposed, the most effective was the addition of the outer shell to the puborectalis-like artificial anal sphincter. The least effective method was the improvement of the transmission structure. Medical titanium alloy and polyetheretherketone were good replacements for nylon-12 that managed to extend the implantation lifetime and yield a moderate improvement.

Our aim was to investigate the effect of avβ3 single-stranded DNA aptamer (avβ3 ssDNA) on vascular restenosis in rats after percutaneous transluminal coronary angioplasty (PTCA) via the Ras-PI3K/MAPK pathway. Sixty Sprague-Dawley rats were randomly divided into six groups: sham-operated, PTCA, PTCA+cilengitide (18 mg/kg, n = 8), and avβ3 ssDNA treatment at 50, 100, and 200 μg/kg. Hematoxylin-eosin staining was performed to evaluate the successful establishment of the PTCA model and to assess the degree of intimal hyperplasia. Immunofluorescence and in situ hybridization were carried out to observe the level of avβ3. Immunohistochemistry was used to detect the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), angiotensin 1 (ANG1), and ANG2. The expression of osteopontin (OPN), focal adhesion kinase (FAK), Ras, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), signal transducer and activator of transcription 1 (STAT1), and GTPase was observed by the western blot and quantitative reverse transcription polymerase chain reaction. Compared with rats subjected to PTCA only, those treated with avβ3 ssDNA showed significantly decreased vascular occlusion rate (P < .05). The protein expression of avβ3, OPN, p-FAK, ANG2, and E-cadherin was significantly increased by avβ3 ssDNA (P < .05), while the levels of ANG1, α-SMA, N-cadherin Ras, MAPK, PI3K, STAT1, and GTPase were significantly decreased (P < .05). Avβ3 ssDNA reduced the proliferation, migration, epithelial-mesenchymal transition, and vascular remodeling of vascular smooth muscle cells, and the mechanism may be related to the Ras-PI3K/MAPK pathway., (© 2019 International Center for Artificial Organ and Transplantation and Wiley Periodicals, Inc.)

Background: Elevated parathyroid hormone (PTH) levels in secondary hyperparathyroidism (SHPT) lead to vascular calcification, which is associated with cardiovascular events and mortality. Increased PTH production is caused by the excessive proliferation of parathyroid gland cells, which is accelerated by abnormal mineral homeostasis. Evocalcet, an oral calcimimetic agent, inhibits the secretion of PTH from parathyroid gland cells and has been used for the management of SHPT in dialysis patients. We observed the effects of evocalcet on ectopic calcification and parathyroid hyperplasia using chronic kidney disease (CKD) rats with SHPT., Methods: CKD rats with SHPT induced by adenine received evocalcet orally for 5 weeks. The calcium and inorganic phosphorus content in the aorta, heart and kidney was measured. Ectopic calcified tissues were also assessed histologically. To observe the effects on the proliferation of parathyroid gland cells, parathyroid glands were histologically assessed in CKD rats with SHPT induced by 5/6 nephrectomy (Nx) after receiving evocalcet orally for 4 weeks., Results: Evocalcet prevented the increase in calcium and inorganic phosphorus content in the ectopic tissues and suppressed calcification of the aorta, heart and kidney in CKD rats with SHPT by reducing the serum PTH and calcium levels. Evocalcet suppressed the parathyroid gland cell proliferation and reduced the sizes of parathyroid cells in CKD rats with SHPT., Conclusions: These findings suggest that evocalcet would prevent ectopic calcification and suppress parathyroid hyperplasia in patients with SHPT., Competing Interests: Evocalcet is the product in development, and Kyowa Kirin Co., Ltd and Mitsubishi Tanabe Pharma Corporation have the ownership of the patents of evocalcet. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic β cell failure. β cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of β-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in β cells not only modulates insulin secretion and β cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in β cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in β cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and β cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of β cells and offer opportunities for the treatment of T2D., Competing Interests: The authors have declared that no competing interests exist.

Ureteric stents have become an indispensable tool in the armamentarium of every urologist. However, they carry their own morbidity resulting mostly from infectious or abacterial fouling and biofilm formation, and/or urothelial hyperplastic reaction. All of these may interact and lead to clinical complications. Many different stent designs and coatings have been proposed. In this study, we focused on the effect of paclitaxel-coated stents on hyperplastic proliferation of ureteral tissue, using as example anastomotic strictures after ureteroureterostomy in a rat model. Human urothelial cells (SV-HUC-1) were used to determine paclitaxel dosages in vitro. Polyurethane stents were coated with a paclitaxel containing biodegradable polymer and studied in a ureteroureterostomy rat model. 48 male 9-week-old Sprague-Dawley rats underwent either sham surgery (n = 16) or ureteroureterostomy with sutured anastomosis, and consecutive stenting with either a paclitaxel-coated or an uncoated stent (16 per group), respectively. The animals received daily intraperitoneal injections of 5-bromo-2-deoxyuridine (20 mg/ml, 100 mg/kg body weight) during the first eight postoperative days, and were sacrificed on day 28. Healing of the ureteral anastomosis and proliferation of urothelial cells was examined histologically and immunohistochemically. In vitro, a concentration of 10 ng/mm 2 paclitaxel can be considered as non-toxic, while still exerting an anti-proliferative effect on urothelial cells. Histologically, typical wound healing processes were seen at the site of the ureteral anastomosis in vivo. Proliferation of urothelial cells was significantly lower in animals with paclitaxel-coated stents compared to those with uncoated stents (LI 41.27 vs. 51.58, p < 0.001). Our results indicate that stenting of ureteral anastomoses with paclitaxel-coated stents can reduce hyperplastic proliferation of ureteral tissue. Paclitaxel-coated stents thus might be able to prevent not only scar-induced postoperative stenosis after reconstructive surgery, but also hyperplastic urothelial reaction in non-anastomotic stent patients as part of their inflammatory response to the foreign material.

Background: Intimal hyperplasia (IH) is the initial lesion of vein graft failure after coronary artery bypass grafting. The weak venous wall is likely one of the primary reasons for IH after exposure to the arterial environment. We investigate whether adventitial collagen cross-link by glutaraldehyde (GA) reinforces the venous wall and then reduces IH., Materials and Methods: Adventitial collagen cross-link by 0.3% GA was performed on the rabbit jugular veins. The degree of cross-link was accessed by tensile test. The jugular vein with or without cross-link was implanted into the carotid artery of rabbit. Vein dilatation at the immediate anastomosis and pathological remodeling of vein graft after 4 wk was assessed., Results: Tensile test indicated that the mechanical property of 3-min cross-linked veins more closely resembled that of the carotid artery. In rabbit arteriovenous graft models, 3-min adventitial collagen cross-link limited overdistension (diameter: 3.24 mm versus 4.65 mm, P < 0.01) at the immediate anastomosis and reduced IH (intima thickness: 78.83 μm versus 140.19 μm, P < 0.01) of vein grafts 4 wk after implantation in the cross-link group as compared with the graft group (without cross-link). Compared with the cross-link group, the expression of proliferating cell nuclear antigen and vascular cell adhesion molecule-1 increased significantly at both the mRNA and protein levels within the graft group (P < 0.01), but the expression of smooth muscle-22α decreased significantly (P < 0.01)., Conclusions: Adventitial collagen cross-link by GA increased the vessel stiffness and remarkably reduced IH in a rabbit arteriovenous graft model., (Copyright © 2019. Published by Elsevier Inc.)

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H + /K + ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Background: Early neointimal hyperplasia of vein graft may be ameliorated via enhancing intravenous surface shear stress. Cellular processes including proliferation, apoptosis and migration of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) may play very important roles in the process of neointimal hyperplasia of vein graft; and mitogen-activated protein kinase (MAPK) pathways including extracellular signal-regulated kinase (ERK1/2) and p38 pathways play vital roles in regulating a large variety of cellular processes. This study evaluated the impacts of shear stress and MAPK pathways on cellular processes of ECs in a co-culture system with VSMCs, and aimed to test the hypothesis that high shear stress suppresses proliferation and migration but promotes apoptosis of ECs co-cultured with VSMCs via down-regulating MAPK pathway., Methods: Primary ECs and VSMCs derived from porcine great saphenous vein were collected, respectively. 4-7 generation of cells were used as work cells. ECs and VSMCs were co-cultured and synchronized under high and low shear stress using Parallel-Plate Flow Chamber system. And then, ECs co-cultured with VSMCs were incubated with U0126 (ERK1/2 inhibitor) or PD98059 (p38 inhibitor) under different shear stress. Proliferation, apoptosis and migration of ECs in a co-culture system with VSMCs were detected by 4,5-dimethyl-2-thiazolyl (MTT) assay and bromodeoxyuridine (BrdU) assay, fluorescent-activated cell sorting (FACS) technique, and Transwell assay separately. Each test repeated 3 times. Additionally, protein expressions of ERK1/2 and p38 MAPK were detected by using Western blot, respectively., Results: Under higher level of shear stress condition, proliferation and migration of ECs co-cultured with VSMCs were suppressed, while cell apoptosis was promoted. And blocking ERK1/2 pathway by U0126 or blocking p38 pathway by PD98059, proliferation and migration of ECs co-cultured with VSMCs were further suppressed, while cell apoptosis was further promoted. Additionally, protein expressions of phosphorylation of ERK1/2 and p38MAPK were decreased under higher level of shear stress condition, and were further reduced by blocking ERK1/2 or p38 pathway under shear stress condition., Conclusions: High shear stress may suppress proliferation and apoptosis of ECs in a co-culture system with VSMCs but promote cell migration via down-regulating ERK1/2 and p38 MAPK pathways.

Inflammatory processes contribute to intimal hyperplasia (IH) and long-term failure of vein grafts used in bypass surgery. Leukocyte recruitment on endothelial cells of vessels during inflammation is regulated by P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1), which also mediates the interaction between platelets and endothelial cells in vein grafts transferred to arteries. However, how this pathway causes IH in vein grafts is unclear. In this study, we used a murine model of vein grafting to investigate P-selectin-mediated platelet adhesion, followed by IH. On the luminal surface of the vein graft, leukocyte recruitment occurred mainly in areas with adhered platelets rather than on endothelial cells without adherent platelets 1 hour after vein grafting. Blockage of either P-selectin or PSGL-1 reduced platelet adhesion and leukocyte recruitment on the luminal surface of vein grafts. Inhibition of the P-selectin pathway in vein grafts significantly reduced platelet-mediated leukocyte recruitment and IH of vein grafts 28 days after surgery. The study demonstrates that functional blockage of the P-selectin/PSGL-1 pathway in the early inflammatory phase after vein grafting reduced leukocyte invasion in the vein graft wall and later IH development. The findings imply an attractive early time window for prevention of vein graft failure by manipulating platelet adhesion., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Hypertrophic scars (HSs) are characterized by fibroblast hyperproliferation and excessive matrix deposition. During wound healing, transforming growth factor (TGF)-β1/Smad signaling acts as a key regulator. As a transcriptional corepressor of TGF-β1/Smads, SnoN is expressed at low levels in many fibrotic diseases due to TGF-β1/Smad-induced degradation. SnoN residue (1-366; SR) is resistant to TGF-β1-induced degradation. However, the expression and role of SR in HSs are unknown. Here, we inhibited TGF-β1/Smad signaling via overexpression of SR to block fibroblast transdifferentiation, proliferation, and collagen deposition during HS formation. Our results showed that SnoN was downregulated in HS fibroblasts (HSFs) owing to TGF-β1/Smad-induced degradation. Overexpression of SR in normal human dermal fibroblasts (NHDFs) and HSFs successfully blocked phosphorylation of Smad2 and Smad3, thereby inhibiting NHDF transdifferentiation and HSF proliferation and reducing type I collagen (ColI) and type III collagen (ColIII) production and secretion. In addition, we applied overexpressed full-length SnoN (SF) and SR to wound granulation tissue in a rabbit model of HSs. SR reduced wound scarring, improved collagen deposition and arrangement of scar tissue, and decreased mRNA and protein expression of ColI, ColIII, and α-smooth muscle actin (α-SMA) more effectively than SF in vivo. These results suggest that SR could be a promising therapy for the prevention of HS.

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.

Extensive proliferation of vascular smooth muscle cell (VSMC) contributes to intimal hyperplasia following vascular injury, in which endoplasmic reticulum stress (ERS) plays a critical role. Intermedin (IMD) is a vascular paracrine/autocrine peptide exerting numerous beneficial effects in cardiovascular diseases. IMD overexpression could alleviate intimal hyperplasia. Here, we investigated whether endogenous IMD protects against intimal hyperplasia by inhibiting endoplasmic reticulum stress. The mouse left common carotid-artery ligation-injury model was established to induce intimal hyperplasia using IMD -/- mice and C57BL/6 J wild-type (WT) mice. Platelet-derived growth factor-BB (PDGF-BB) was used to stimulate the proliferation of VSMC. IMD -/- mice displayed exacerbated intimal hyperplasia induced by complete ligation of the left carotid artery at 14 d and 28 d compared to WT mice. However, IMD-deficiency had no effect on blood pressure, plasma triglyceride, and fasting blood glucose levels in mice. Furthermore, VSMCs derived from IMD -/- mice showed increased cell proliferation and dramatically elevated levels of glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), ATF6 mRNA under PDGF-BB treatment compared to WT mice-derived VSMCs. In addition, exogenous administration of IMD significantly attenuated PDGF-BB-induced cell proliferation and GRP78, phosphorylase-inositol requiring enzyme 1α, ATF4, and ATF6 protein levels. Thus, endogenous IMD may counteract ERS to exert protective role in response to vascular injury and IMD is expected to be a therapeutic target for the prevention and treatment of restenosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The colon is partly controlled by myenteric and submucosal plexuses, which respond to stress and lead to some gastrointestinal disorders. These plexuses play roles in irritable bowel syndrome. Patients suffering from this syndrome can be treated with some antidepressants, including sertraline and nortriptyline., Aims: The primary aim of study was to compare the effect of a sertraline and a nortriptyline on the structural changes of the enteric neurons after stress exposure in both sexes. The secondary objectives were to evaluate the effects of stress on the submucosal and myenteric plexuses., Methods: Male and female Sprague-Dawley rats were assigned to four subgroups. The first subgroup received no stress. The other three subgroups received chronic variable stress (CVS) and were given phosphate buffer, sertraline (10 mg/kg/day), or nortriptyline (10 mg/kg/day). After 45 days, the neuron number in their colon plexuses was estimated using the stereologic method., Results: The number of neurons increased by 40-51% in the submucosal plexus and by 57-69% in the myenteric plexus in the CVS group compared with the control group (p < 0.002) without any sex preference. The increment was significantly higher in the myenteric plexus than in the submucosal plexus (p < 0.05). Moreover, co-treatment of stressed rats with sertraline and nortriptyline could prevent the cellular hyperplasia of the plexuses, with more effective action for sertraline (p < 0.02)., Conclusions: Stress exposure for 45 days induced hyperplasia of the colon's enteric plexuses in both sexes. However, these drugs could prevent the changes, with a more effective action for sertraline.

The polyherbal blend Zyflamend™ has been shown to have anti-inflammatory properties and attenuate inflammatory-modulated pathologies. Fish oils have also been shown to have cardioprotective properties. However, the beneficial effects of their combination have not been investigated. Intimal hyperplasia (IH), a pathological remodeling response of a vessel to injury, is heavily regulated by an immune-mediated reaction. The objective of this study was to determine if dietary supplementation with Zyflamend and/or Wholemega could affect inflammatory-dependent vascular remodeling mechanisms when provided at human equivalent doses. Based on their anti-inflammatory properties and protective benefits demonstrated in previous pre-clinical studies, we hypothesized administration of these supplements would prevent IH in an animal model of vascular injury. The diets of aged male rats were supplemented with human equivalent doses of Zyflamend (Zyf) and/or Wholemega (WMega) or placebo (Plac) for 1wk prior to balloon angioplasty (BA)-induced injury of the left carotid artery. At 28d post-injury morphometric analysis of carotid tissue revealed IH was decreased in Zyf + WMega animals compared to placebo, while Zyf or WMega independently had no significant effect. Serum cytokine screening indicated injury-induced interleukin family isoforms, interferon-γ, and macrophage inflammatory proteins were downregulated by Zyf + WMega. Immunohistochemical staining for monocyte/macrophage phenotypic markers revealed that while overall monocyte/macrophage vessel infiltration was not affected, Zyf + WMega limited the alternative differentiation of M2 macrophages and reduced the presence of myofibroblasts in the injured vessel wall. In summary, dietary supplementation with Zyf + WMega attenuated the acute inflammatory response following vascular injury and inhibited IH development in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Due to their relatively good biocompatibility and inactivity, titanium oxide films (Ti-O) are used in the coating of coronary stents, which reduces metal corrosion, slows metal ion release, and improves endothelial cell (EC) compatibility. Here, we report further functionalizing Ti-O with biological cues for selective endothelialization. Selenocystine with an l- or a d-enantiomer was first immobilized on the Ti-O film via polydopamine to generate nitric oxide (NO) endogenously, which inhibited smooth muscle cell (SMC) proliferation, followed by the grafting of a functional KREDVC peptide to induce EC adhesion. The synergistic effects of the immobilized KREDVC, surface chirality, and NO generation on selective endothelialization were investigated. The results showed that the surface chirality of the l-enantiomer and KREDVC grafting significantly enhanced the attachment and growth of ECs compared to SMCs. An in vivo study showed von Willebrand factor expression was increased and neointimal hyperplasia was significantly decreased in samples with l-selenocystine immobilization and KREDVC grafting. In summary, these findings provide new insights on the surface modification of cardiovascular implants with selective endothelialization., (Copyright © 2019. Published by Elsevier B.V.)

We established a rabbit iliac artery restenosis model to explore the impact of Telmisartan on the expression of Connexin43 (Cx43) and neointimal hyperplasia. Thirty New Zealand white rabbits were randomly divided into three groups: control group (n = 10), restenosis group (n = 10), and Telmisartan group (n = 10). The restenosis model was established by high-cholesterol diet combined with double-balloon injury of iliac arteries. In addition, Telmisartan at 5 mg/(kg day) was administered to the rabbits of Telmisartan group on the second day after the second balloon injury. All rabbits were killed at the end of the experiment followed by institution policy. Before sacrifice, blood samples were obtained to test serum angiotensinII (AngII). Iliac arteries were isolated for morphological analysis and determining the expression of Cx43 by HE staining, immunohistochemical analysis, reverse transcription-polymerase chain reaction (RT-PCR), and Western Blotting analysis. Then, the local AngII levels of arteries were measured by radioimmunoassay. As compared with controls, the expression of Cx43 mRNA (0.98 ± 0.08) vs. (1.27 ± 0.17), P < 0.01), and Cx43 protein [(0.75 ± 0.08) vs. (0.90 ± 0.08), P < 0.05] of restenosis group were increased, which were significantly higher than those of Telmisartan group [Cx43 mRNA: (1.27 ± 0.17) vs. (1.00 ± 0.20), P < 0.01; Cx43 protein: (0.90 ± 0.08) vs. (0.82 ± 0.05), P < 0.05]. Furthermore, The intima thickness [(266.12 ± 70.27) vs. (2.85 ± 0.19) μm, P < 0.01] and the local AngII [(115.6 ± 15.7) vs. (90.1 ± 7.7), P < 0.05] of restenosis group were raised when compared with controls. Telmisartan group exhibited thinner intima compared with restenosis group [(68.22 ± 24.37) vs. (266.12 ± 70.27), P < 0.01]. However, the local AngII levels between these two groups were approximate. In addition, the plasma concentration of AngII was not significantly different among three groups. In conclusion, Telmisartan can inhibit the expression of connexin43 and neointimal hyperplasia in iliac artery restenosis model.

The aim of the present study was to investigate the correlation between human papillomavirus (HPV) type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia in order to explore methods for preventing glandular thickening mammary gland hyperplasia. A total of 240 patients with glandular thickening mammary gland hyperplasia who were treated by surgery in our hospital from January 2012 to June 2017 were enrolled in the present study. The hyperplastic breast tissue and adjacent normal breast tissue were taken to test HPV type 6/11 and 16/18 infections using conventional PCR and in situ hybridization techniques. The correlations between HPV type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia were analyzed using statistical methods of chi-square test. The infection rates of HPV type 6/11 and 16/18 in the hyperplastic breast tissue were 31.95% and 34.91%, respectively and 11.83% and 14.79% in the normal breast tissue, respectively. The differences were statistically significant (all p&lt;0.05). HPV type 6/11 and 16/18 infections may be closely related to the development of glandular thickening mammary gland hyperplasia, and may be one of the causes of glandular thickening mammary gland hyperplasia.

Although the efficacy of external stents for vein grafts in coronary artery bypass grafting has been recognized, the ideal diameter and material of the stent remain controversial. We created a new external stent made of soft polyester mesh and performed an animal experiment using canines. Bilateral saphenous vein grafts were interposed in the bilateral common carotid artery of 10 beagles. The grafts in the left carotid artery were designated as the control group, and those in the right rolled by a soft polyester mesh external stent were designated as mesh group. Two of the 10 animals were sacrificed due to severe wound infection. The other eight were observed by echography for 6 months, and then grafts were extracted and thickness of the neointima of the grafts was measured. The control group showed 146% ± 26% postoperative enlargement of the internal diameter of the vein grafts after 6 months, whereas the mesh group showed only 115% ± 15% after the same duration (P = 0.0003). The median thickness of the neointima in the mesh group (170 µm [range: 150-190]) was significantly thinner than that in the control group (260 µm [range: 220-310], P < 0.0001). Some degree of correlation between the thickness of neointima and proportion of enlargement was noted (r = 0.518, P = 0.0024). A soft polyester mesh external stent for vein grafts successfully suppressed the enlargement of the vein grafts and thickness of the neointima after 6 months., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019., (© 2018 International Union of Biochemistry and Molecular Biology.)

Aims: The proliferation of VSMCs is the pathologic basis for intimal hyperplasia after angioplasty in diabetic patients. Translocator protein (TSPO), located in the outer mitochondrial membrane, has been found to regulate redox intermediate components in cell dysfunction. We hypothesized that TSPO may regulate VSMC proliferation and migration, and be involved in the intimal hyperplasia after angioplasty in diabetes., Materials and Methods: Cell proliferation was measured by cell counting and MTT assays. Cell migration was measured by Transwell® and scratch-wound assays. TSPO expression in arteries of rats and high glucose-treated A10 cells were detected by immunoblotting and immunofluorescence staining. Neointimal formation of carotid artery was induced by balloon injury in type 2 diabetic rat., Key Findings: TSPO expression was increased in the arterial samples from diabetic rats and A10 cells treated with high glucose. Down-regulation of TSPO expression by siRNA decreased the high-glucose-induced VSMC proliferation and migration in A10 cells. This phenomenon could be simulated by using TSPO ligands, PK 11195 and Ro5-4864. cGMP/PKG signals were involved in the TSPO ligand action, since in the presence of cGMP or PKG inhibitor ODQ or KT5823 respectively, the effect of PK 11195 on VSMC proliferation was blocked. Furthermore, PK 11195 significantly inhibited neointimal formation by the inhibition of VSMC proliferation., Significance: This study suggests that TSPO inhibition suppresses the proliferation and migration of VSMCs induced by hyperglycemia, consequently, preventing atherosclerosis and restenosis after angioplasty in diabetic conditions. TSPO may be a potential therapeutic target to reduce arterial remodeling induced by angioplasty in diabetes., (Copyright © 2019. Published by Elsevier Inc.)

Background: Intimal hyperplasia is the major therapeutic concern after percutaneous coronary intervention. The aim of this study is to investigate effects of 2,3,4',5-tetrahydroxystilbene-2-O-β-D glucoside (TSG) on intimal hyperplasia and the underling mechanisms through attenuating the expressions of stromal cell-derived factor-1α (SDF-1α)/CXCR4, stem cell factor (SCF)/c-kit and fractalkine (FKN)/CX3CR1, and through promoting re-endothelialization with vascular endothelial growth factor (VEGF)., Method: Rats were operated with carotid artery balloon injury. The treatment groups were gavaged with 50 and 100 mg/kg/d of TSG. After 10 days of treatment, carotid artery pathological changes were evaluated by histology. Serum levels of SDF-1α, SCF, FKN and VEGF were detected by enzyme linked immunosorbent assay. The protein expressions of the receptors c-kit, CXCR4, CX3CR1, as well as CD34 and proliferating cell nuclear antigen (PCNA) were detected by immunochemistry., Results: TSG dose-dependently inhibited balloon injury-induced intimal hyperplasia, as evidenced by reducing neointima area (NIA), neointima area/media area (NIA/MA), neointima area/internal elastic area (NIA/IELA), and by decreasing the protein expression of PCNA. TSG reduced serum levels of SDF-1α, SCF and FKN, and it also decreased the expressions of the corresponding receptors c-kit, CXCR4, CX3CR1 in neointima. Importantly, the level of VEGF in peripheral blood and the expression of CD34 in vascular walls were increased to promote re-endothelialization., Conclusions: This study clearly demonstrated that TSG was effective in inhibiting intimal hyperplasia, and this effect was mediated, at least in part, through the SCF/c-kit, SDF-1α/CXCR4 and FKN/CX3CR1 axes. Importantly, TSG could increase VEGF and CD34 to promote endothelial repair., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)