Potential anti-arteriovenous malformations effect of sirolimus on angiogenesis induced by maxillofacial venous hypertension
Li XiaoZhipeng GuiYifeng HanXi YangZhenfeng WangLianzhou ZhengLiming ZhangDeming WangXindong FanLixin Su
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Abstract Background: This study aimed to explore the possible role and mechanism of venous hypertension (VH) in the occurrence and development of arteriovenous malformations (AVMs) and to study the therapeutic effect of VH regulation on AVMs to provide insight into AVM pathogenesis and explore new treatments. Methods: Maxillofacial VH models were established by cervical vascular anastomosis. Osteogenesis and angiogenesis in the model rats were analysed by imaging and histology, and the inhibitory effects of intraperitoneal (ip) sirolimus injection on angiogenesis were detected. The effect of sirolimus on the biological behaviour of human umbilical vein endothelial cells (HUVECs) cultured in vitro and mechanism of sirolimus were detected by cytology. Result: The local microvessel density increased, the vessels showed tortuous dilation, and mRNA and protein levels of angiogenesis-related genes were increased in venous hypertension environment. These phenomena were alleviated or eliminated by ip injection of a sirolimus solution. Sirolimus inhibited proliferation, tubule formation, migration, invasion, angiogenesis-related gene transcription and translation, and phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrate proteins S6K1 and 4EBP1. Conclusions: Abnormal angiogenesis caused by VH is related to abnormal activation of the mTOR pathway, which is important in regulating local angiogenesis; sirolimus inhibited hypertension-induced excessive angiogenesis in vivo and in vitro through the mTOR signalling pathway. This study provides a basis for further mechanistic study of AVM formation and insight into sirolimus as a possible target drug for AVM management.Keywords:
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This article summarized the application of sirolimus(rapamycin)in drug-eluting stent(DES) and its working mechanism. A lot of clinical studies have shown sirolimus eluting stent(SES)reduced restenosis rate to less than 10% but sirolimus has also caused lots of problems in the DES. The pharmacological study of sirolimus would help further improvements in SES.
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Objective To explore the time-effect of damage in human umbilical vein endothelial cell lines induced by Trichlorfon and to analyze its mechanism.Methods HUVECs-12 were cultured in DMEM containing Trichlorfon for 24 h,the growth inhibition was measured by MTT assay.Cells were incubated in IC50 concentration Trichlorfon(400 μmol/L) for different times(0,4,6,8,12,24,48 h)) to test the time-effect of damage in human umbilical vein endothelial cells;the level of malondialde-hyde(MDA) in supernatant-conditioned media was monitored by thiobituric acid reaction(TBA).Results Trichlorfon inhibited HUVECs-12 growth in a dose-dependent manner and increased the production of MDA.Conclusion Trichlorfon can induce damage in human umbilical vein endothelial cells.
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Angiogenesis, a formation of neovessels, is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of such endogenous regulators of angiogenesis have been found in the body. Recently, vasohibin-1 (VASH1) was isolated as a negative feedback regulator of angiogenesis produced by endothelial cells (ECs) and subsequently vasohibin-2 (VASH2) as a homologue of VASH1. It was then explored that VASH1 is expressed in ECs to terminate angiogenesis, whereas VASH2 is expressed in cells other than ECs to promote angiogenesis in the mouse model of angiogenesis. This review will focus on the vasohibin family members, which are novel regulators of angiogenesis.
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Vascular anomalies (VAs) may be associated with significant morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of sirolimus (rapamycin) in the treatment of children and young adults with complicated VAs. A retrospective chart was created that included 19 patients treated with sirolimus for complicated VAs. Concurrently, a search of the PubMed database for VA cases treated with sirolimus was conducted. Descriptive analysis was performed and the efficiency rate of sirolimus was calculated. This retrospective study included 19 patients, 17 of whom were treated with oral sirolimus and 2 with topical sirolimus. Clinical improvement occurred in 15 patients (79%).?One patient experienced near-complete resolution. Only 2 patients showed poor response and discontinued treatment. The literature review analysed 150 cases of VA treated with sirolimus. Sirolimus was efficient in 85% of cases, including 5 cases of complete resolution. Sirolimus appears to be an effective and safe treatment for children and young adults with complicated VAs.
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Objective: To explore the molecular mechanism of the proliferation of human umbilical vein endothelial cells induced by AngⅡ.Methods: The lines of human umbilical vein endothelial cell cultured in vitro were divided into 3 groups which were treated by AngⅡ, AngⅡ+NAC, and normal culture medium respectively. First we observed the proliferous effect of human umbilical vein endothelial cells induced by AngⅡ at different concentration at different time with biochemical methods. Then the contents of ROS(·OH) in 3 groups were detected by spectrophotometer. Finally we detected the related gene expression in the process of human umbilical vein endothelial cells proliferation via the technique of genechips.Results: Human umbilical vein endothelial cells incubated with AngⅡ(0.03125～1μmol/L ) for 12 hours increased the proliferation rate (P0.05);the negative correlation between proliferation rate and the contents of ROS(·OH)(r=-0.8, P0.01) was significant;NAC can reduce the content of ROS(·OH) and inhibit the proliferation of human umbilical vein endothelial cells;The technique of genechips analysis suggests that the genes expression related to proliferation such as ERK, Akt, CCN and PCNA increased, while the gene expression related to apoptosis such as DR6, Caspases6 BAK1 and PDCD8 decreased when human umbilical vein endothelial cell were induced by AngⅡ(0.0625μmol/L) for 12 hours; In contrast, when human umbilical vein endothelial cells were induced by AngⅡ(1μmol/L) for 12 hours, we can obtain reverse results. Conclusion: Human umbilical vein endothelial cells induced by AngⅡcan produce ROS(·OH).The target gene expression related to proliferation of human umbilical vein endothelial cells may be mediated by ROS(·OH), ROS(·OH) may be the molecules which play an important role in the signal transduction and gene expression of proliferation.
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Angiogenesis 为许多生理、病理学的过程是很重要的。然而， angiogenesis 的分子的机制是不清楚的。阐明 angiogenesis 并且到的分子的机制为 angiogenesis 依赖的疾病开发处理，建立是必要的一在 vitro angiogenesis 合适模型。在这研究，我们基于一台 microfluidic 设备在 vitro angiogenesis 模型创造了一篇小说。我们的模型提供一在里面为 endothelial 房间(EC ) 的象 vivo 一样微型环境文化和监视器到在他们在实时的微型环境的变化的 EC 的反应。为了为研究 angiogenesis， EC 增长上的 pro-angiogenic 因素的效果，迁居和像试管的结构形成评估这台 microfluidic 设备的潜力，被调查。我们的结果证明在 3D 矩阵的 EC 的增长率被 pro-angiogenic 因素显著地支持(随 59.12% 的增加) 。与 pro-angiogenic 因素坡度的刺激，方向性地从低集中移植进 Matrigel 到高集中并且因而的 EC 形成了多房间弦和像试管的结构。这些结果建议设备能为阐明提供一个合适的平台 angiogenesis 并且为为 angiogenesis 依赖的疾病屏蔽 pro-angiogenic 或 anti-angiogenic 药的机制。
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Current immunosuppressive therapies are effective but can be associated with significant adverse reactions. Sirolimus works differently from the immunosuppressants currently available, and except for increased lipid levels, the adverse reaction profile of sirolimus does not appear to overlap to any great extent with that associated with cyclosporine or tacrolimus. While additional research is needed, the initial clinical data in kidney recipients suggest that sirolimus, in combination with cyclosporine or tacrolimus, might have the potential to reduce the frequency of rejection episodes, permit reductions in cyclosporine or tacrolimus dosage, and permit steroid withdrawal (Kelly, 1999).
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