Recently, the team led by Professor Wang Guixue of the School of Bioengineering of Chongqing University made astonishing breakthroughs in research of bio-mechanical mechanism of action of arsenic trioxide drug-eluting stent for inhibiting in-stent restenosis. The research findings were published in Part 2, Volume 6 of Bioactive Materials (IF: 14.593), a top journal of Zone 1 in the biochemical area. This paper reveals the new bio-mechanical mechanism of action of “YAP mediated arsenic trioxide regulating phenotypic transformation of vascular smooth muscle cells for inhibiting in-stent restenosis”.

ATO, also known as arsenic, is a typical "dual-purpose pharmaceutical-toxic" compound. In recent years, ATO has shown the efficacy of "rectifying” pathological cells in curing promyelocytic leukemia, eliminating cancer stem cells and restoring the tumor suppressive function of structural mutant p53. In the prevention and treatment of atherosclerosis (AS), ATO was introduced into the medical world because it can inhibit the malignant proliferation of vascular smooth muscle cells (VSMCs). However, there are only few reports on ATO in VSMCs phenotype reversal differentiation.

Dedifferentiation of VSMCs can increase cell proliferation, which is the main cause of vascular restenosis after stent implantation. This study was the first to reveal that ATO can promote the phenotypic differentiation of VSMCs, accompanied by the changes of cytoskeleton, elastic modulus and other cellular mechanical properties. Transcriptome sequencing analysis and related biochemical molecular techniques preliminarily discovered that cytoskeleton F-actin and mechanical response factor Yap could mediate the mechanism of ATO promoting the phenotypic differentiation of VSMCs. The mechanism of ATO on VSMCs phenotype transformation was studied using New Zealand white rabbit intravascular stent implantation and VSMCs phenotype transformation model in vitro, which further confirmed that YAP could partially mediate ATO to regulate VSMCs phenotype transformation.

This study was about vascular restenosis and focused on the "frontier" research direction of promoting the normalization of diseased cells, and expanded the pharmacological category of old drugs and new uses of ATO in the field of AS based on the mechanical properties and biological properties of cells. It mainly revealed the mechanism of ATO regulating the transformation of VMSCs from the synthetic type to mature contractile type in the process of inhibiting restenosis in stent, and provided new ideas and strategies for intervention or reversal of neointimal hyperplasia, AS and other vascular remodeling diseases.

Wang Guixue is the corresponding author of the paper. Researcher Qiu Juhui is the corresponding co-author of the paper. Doctoral candidate Zhao Yinping is the first author of the paper. Chongqing Medical University, Rhythmtronic, Engineering Research Center in Biomaterials, Sichuan University, and Newcastle University are research partners. This Project has been supported by the National Natural Science Foundation (31971242, 31701275) and the National Key R&D Program (2016YFC1102305).

Wang Guixue's team has been engaged in the research of vascular biomechanics and hemorheology, intravascular stents and artificial blood vessels for a long time. It has revealed that the domestic arsenic trioxide (ATO) drug-eluting stents hailed as "international original" by the Ministry of Science and Technology are a kind of endothelium-friendly stents. Compared with the commonly used rapamycin drug-eluting stent, this stent can also inhibit the occurrence of in stent restenosis and faster promote the healing and re-endothelialization of vascular damaged tissue. The research results were published in the world well-known journal Advanced Healthcare Materials in August 2018.

In recent five years, the team led by Wang Guixue has made breakthroughs in a number of fields, including neurovascular coupling, vascular biomechanics and tissue repair materials, nano-drug treatment of atherosclerotic cardiovascular diseases, and has successively published more than 120 research papers in international high-level journals such as Nature Neuroscience, Advanced Science and Journal of Biomechanics. The innovative achievements have been well received and cited by many professors from Cambridge University, King's College London, University of Zurich, Stanford University, Harvard University, Massachusetts Institute of Technology, Peking University, Zhejiang University and University of Macao in China. Professor Wang Guixue was included in Elsevier's list of highly cited scholars in China in 2019 and 2020 (Biomedical Engineering).

Information on the paper:

YP Zhao, GC Zang, TY Yin, XY Ma, LF Zhou, LG Wu, R Daniel, YB Wang, JH Qiu, GX Wang. A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway. Bioactive Materials. 2021, 6(2): 375-385.

Link of the paper:

https://www.sciencedirect.com/science/article/pii/S2452199X20301912