Temporal regulation of notch activation improves arteriovenous fistula maturation

Author:

Guo Qunying,Chen Guang,Cheng Hunter,Qing Ying,Truong Luan,Ma Quan,Wang Yun,Cheng Jizhong

Abstract

Abstract Background Arteriovenous fistula (AVF) maturation is a process involving remodeling of venous arm of the AVFs. It is a challenge to balance adaptive AVF remodeling and neointima formation. In this study we temporally controlled Notch activation to promote AVF maturation while avoiding neointima formation. Methods Temporal Notch activation was controlled by regulating the expression of Notch transcription factor, RBP-Jκ, or dnMAML1 (dominant negative MAML2) in vascular smooth muscle cells (VSMCs). AVF mouse model was created and VSMC phenotype dynamic changes during AVF remodeling were determined. Results Activated Notch was found in the nuclei of neointimal VSMCs in AVFs from uremic mice. We found that the VSMCs near the anastomosis became dedifferentiated and activated after AVF creation. These dedifferentiated VSMCs regained smooth muscle contractile markers later during AVF remodeling. However, global or VSMC-specific KO of RBP-Jκ at early stage (before or 1 week after AVF surgery) blocked VSMC differentiation and neointima formation in AVFs. These un-matured AVFs showed less intact endothelium and increased infiltration of inflammatory cells. Consequently, the VSMC fate in the neointima was completely shut down, leading to an un-arterialized AVF. In contrast, KO of RBP-Jκ at late stage (3 weeks after AVF surgery), it could not block neointima formation and vascular stenosis. Inhibition of Notch activation at week 1 or 2, could maintain VSMC contractile markers expression and facilitate AVF maturation. Conclusions This work uncovers the molecular and cellular events in each segment of AVF remodeling and found that neither sustained increasing nor blocking of Notch signaling improves AVF maturation. It highlights a novel strategy to improve AVF patency: temporally controlled Notch activation can achieve a balance between adaptive AVF remodeling and neointima formation to improve AVF maturation. Translational perspective Adaptive vascular remodeling is required for AVF maturation. The balance of wall thickening of the vein and neointima formation in AVF determines the fate of AVF function. Sustained activation of Notch signaling in VSMCs promotes neointima formation, while deficiency of Notch signaling at early stage during AVF remodeling prevents VSMC accumulation and differentiation from forming a functional AVFs. These responses also delay EC regeneration and impair EC barrier function with increased inflammation leading to failed vascular remodeling of AVFs. Thus, a strategy to temporal regulate Notch activation will improve AVF maturation.

Funder

National Institute of Health

Publisher

Springer Science and Business Media LLC

Subject

General Biochemistry, Genetics and Molecular Biology,General Medicine

Reference47 articles.

1. Schon D, Blume SW, Niebauer K, Hollenbeak CS, de Lissovoy G. Increasing the use of arteriovenous fistula in hemodialysis: economic benefits and economic barriers. Clin J Ame Soc Nephrol: CJASN. 2007;2:268–76.

2. Crowther MA, Clase CM, Margetts PJ, Julian J, Lambert K, Sneath D, Nagai R, Wilson S, Ingram AJ. Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: a randomized controlled trial. J Am Soc Nephrol. 2002;13:2331–7.

3. Dember LM, Beck GJ, Allon M, Delmez JA, Dixon BS, Greenberg A, Himmelfarb J, Vazquez MA, Gassman JJ, Greene T, Radeva MK, Braden GL, Ikizler TA, Rocco MV, Davidson IJ, Kaufman JS, Meyers CM, Kusek JW, Feldman HI. Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis. JAMA. 2008;299:2164–71.

4. Veterans Affairs Cooperative Study Group on Hemodialysis Access Graft Thrombosis, Kaufman JS, O’Connor TZ, Zhang JH, Cronin RE, Fiore LD, Ganz MB, Goldfarb DS, Peduzzi PN. Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis. J Am Soc Nephrol. 2003;14:2313–21.

5. Fish Oil Inhibition of Stenosis in Hemodialysis Grafts Study Group, Lok CE, Moist L, Hemmelgarn BR, Tonelli M, Vazquez MA, Dorval M, Oliver M, Donnelly S, Allon M, Stanley K. Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA. 2012;307:1809–16.

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3