Survivin regulates intracellular stiffness and extracellular matrix production in vascular smooth muscle cells

Author:

Krajnik Amanda1,Nimmer Erik2ORCID,Brazzo Joseph A.1,Biber John C.1ORCID,Drewes Rhonda1ORCID,Tumenbayar Bat-Ider3ORCID,Sullivan Andra2,Pham Khanh4ORCID,Krug Alanna2ORCID,Heo Yuna12ORCID,Kolega John1ORCID,Heo Su-Jin5ORCID,Lee Kwonmoo67ORCID,Weil Brian R.8ORCID,Kim Deok-Ho9ORCID,Gupte Sachin A.10ORCID,Bae Yongho12ORCID

Affiliation:

1. Department of Pathology and Anatomical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo 1 , Buffalo, New York 14203, USA

2. Department of Biomedical Engineering, School of Engineering and Applied Sciences, University at Buffalo 2 , Buffalo, New York 14260, USA

3. Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo 3 , Buffalo, New York 14203, USA

4. Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo 4 , Buffalo, New York 14203, USA

5. Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania 5 , Philadelphia, Pennsylvania 19104, USA

6. Vascular Biology Program, Boston Children's Hospital 6 , Boston, Massachusetts 02115, USA

7. Department of Surgery, Harvard Medical School 7 , Boston, Massachusetts 02115, USA

8. Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo 8 , Buffalo, New York 14203, USA

9. Department of Biomedical Engineering, Johns Hopkins University 9 , Baltimore, Maryland 21205, USA

10. Department of Pharmacology, New York Medical College 10 , Valhalla, New York 10595, USA

Abstract

Vascular dysfunction is a common cause of cardiovascular diseases characterized by the narrowing and stiffening of arteries, such as atherosclerosis, restenosis, and hypertension. Arterial narrowing results from the aberrant proliferation of vascular smooth muscle cells (VSMCs) and their increased synthesis and deposition of extracellular matrix (ECM) proteins. These, in turn, are modulated by arterial stiffness, but the mechanism for this is not fully understood. We found that survivin is an important regulator of stiffness-mediated ECM synthesis and intracellular stiffness in VSMCs. Whole-transcriptome analysis and cell culture experiments showed that survivin expression is upregulated in injured femoral arteries in mice and in human VSMCs cultured on stiff fibronectin-coated hydrogels. Suppressed expression of survivin in human VSMCs significantly decreased the stiffness-mediated expression of ECM components related to arterial stiffening, such as collagen-I, fibronectin, and lysyl oxidase. By contrast, expression of these ECM proteins was rescued by ectopic expression of survivin in human VSMCs cultured on soft hydrogels. Interestingly, atomic force microscopy analysis showed that suppressed or ectopic expression of survivin decreases or increases intracellular stiffness, respectively. Furthermore, we observed that inhibiting Rac and Rho reduces survivin expression, elucidating a mechanical pathway connecting intracellular tension, mediated by Rac and Rho, to survivin induction. Finally, we found that survivin inhibition decreases FAK phosphorylation, indicating that survivin-dependent intracellular tension feeds back to maintain signaling through FAK. These findings suggest a novel mechanism by which survivin potentially modulates arterial stiffness.

Funder

American Heart Association

National Heart, Lung, and Blood Institute

Publisher

AIP Publishing

Subject

Biomedical Engineering,Biomaterials,Biophysics,Bioengineering

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