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Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis

文献类型：期刊论文

作者Wang, Jin7,8,9,10; Xie, Si-an6,7,8,9,10; Li, Ning3,4,5; Zhang, Tao2; Yao, Weijuan10; Zhao, Hucheng1; Pang, Wei10; Han, Lili10; Liu, Jiayu7,8,9,10; Zhou, Jing7,8,9,10
刊名BIOACTIVE MATERIALS
出版日期2022-11-01
卷号17页码:406-424
关键词Matrix stiffness Inflammation DDR1 DNMT1 Mechanotransduction
DOI10.1016/j.bioactmat.2022.01.012
通讯作者Zhou, Jing(jzhou@bjmu.edu.cn)
英文摘要Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvimnments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.
WOS关键词DOMAIN RECEPTOR 1 ; DNA METHYLATION ; PHENOTYPE ; BINDING ; OVEREXPRESSION ; ACTIVATION ; EXPRESSION ; MIGRATION ; HISTONE ; P53
资助项目National Natural Science Foundation of the China[91949112] ; National Natural Science Foundation of the China[81974052] ; National Natural Science Foundation of the China[81921001] ; National Natural Science Foundation of the China[91939302] ; National Natural Science Foundation of the China[31870930] ; Peking University Health Science Center, the Plan for Strengthening the Basic Research[BMU2020JC002]
WOS研究方向Engineering ; Materials Science
语种英语
WOS记录号WOS:000788643400002
资助机构National Natural Science Foundation of the China ; Peking University Health Science Center, the Plan for Strengthening the Basic Research
源URL[http://dspace.imech.ac.cn/handle/311007/89012]  
专题力学研究所_国家微重力实验室
通讯作者Zhou, Jing
作者单位1.Tsinghua Univ, Sch Aerosp Engn, Inst Biomech & Med Engn, Beijing, Peoples R China
2.Peking Univ Peoples Hosp, Dept Vasc Surg, Beijing, Peoples R China
3.Univ Chinese Acad Sci, Sch Engn Sci, Beijing, Peoples R China
4.Chinese Acad Sci, Beijing Key Lab Engn Construct & Mechanobiol, Inst Mech, Beijing, Peoples R China
5.Chinese Acad Sci, Ctr Biomech & Bioengn, Inst Mech, Key Lab Micrograv,Natl Micrograv Lab, Beijing, Peoples R China
6.Capital Med Univ, Beijing Friendship Hosp, Natl Clin Res Ctr Digest Dis, Beijing Digest Dis Ctr,Dept Gastroenterol,Beijing, Beijing, Peoples R China
7.Peking Univ, Beijing Key Lab Cardiovasc Receptors Res, Beijing, Peoples R China
8.Peking Univ, Natl Hlth Commiss Key Lab Cardiovasc Mol Biol & R, Beijing, Peoples R China
9.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
10.Peking Univ, Hemorheol Ctr, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jin,Xie, Si-an,Li, Ning,et al. Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis[J]. BIOACTIVE MATERIALS,2022,17:406-424.
APA Wang, Jin.,Xie, Si-an.,Li, Ning.,Zhang, Tao.,Yao, Weijuan.,...&李宁.(2022).Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis.BIOACTIVE MATERIALS,17,406-424.
MLA Wang, Jin,et al."Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis".BIOACTIVE MATERIALS 17(2022):406-424.

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来源：力学研究所

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