| Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis | |
Wang, Jin1,2,3,4; Xie, Si-an1,2,3,4,5; Li N(李宁)6,7,8 ; Zhang, Tao9; Yao, Weijuan1; Zhao, Hucheng10; Pang, Wei1; Han, Lili1; Liu, Jiayu1,2,3,4; Zhou, Jing1,2,3,4
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| Corresponding Author | Zhou, Jing([email protected]) |
| Source Publication | BIOACTIVE MATERIALS
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| 2022-11-01 | |
| Volume | 17Pages:406-424 |
| Abstract | 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. |
| Keyword | Matrix stiffness Inflammation DDR1 DNMT1 Mechanotransduction |
| DOI | 10.1016/j.bioactmat.2022.01.012 |
| Indexed By | SCI |
| Language | 英语 |
| WOS ID | WOS:000788643400002 |
| WOS Keyword | DOMAIN RECEPTOR 1 ; DNA METHYLATION ; PHENOTYPE ; BINDING ; OVEREXPRESSION ; ACTIVATION ; EXPRESSION ; MIGRATION ; HISTONE ; P53 |
| WOS Research Area | Engineering ; Materials Science |
| WOS Subject | Engineering, Biomedical ; Materials Science, Biomaterials |
| Funding Project | 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] |
| Funding Organization | National Natural Science Foundation of the China ; Peking University Health Science Center, the Plan for Strengthening the Basic Research |
| Classification | 一类 |
| Ranking | 3 |
| Contributor | Zhou, Jing |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://dspace.imech.ac.cn/handle/311007/89013 |
| Collection | 微重力重点实验室 |
| Affiliation | 1.Peking Univ, Hemorheol Ctr, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing, Peoples R China; 2.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China; 3.Peking Univ, Natl Hlth Commiss Key Lab Cardiovasc Mol Biol & R, Beijing, Peoples R China; 4.Peking Univ, Beijing Key Lab Cardiovasc Receptors Res, Beijing, Peoples R China; 5.Capital Med Univ, Beijing Friendship Hosp, Natl Clin Res Ctr Digest Dis, Beijing Digest Dis Ctr,Dept Gastroenterol,Beijing, Beijing, Peoples R China; 6.Chinese Acad Sci, Ctr Biomech & Bioengn, Inst Mech, Key Lab Micrograv,Natl Micrograv Lab, Beijing, Peoples R China; 7.Chinese Acad Sci, Beijing Key Lab Engn Construct & Mechanobiol, Inst Mech, Beijing, Peoples R China; 8.Univ Chinese Acad Sci, Sch Engn Sci, Beijing, Peoples R China; 9.Peking Univ Peoples Hosp, Dept Vasc Surg, Beijing, Peoples R China; 10.Tsinghua Univ, Sch Aerosp Engn, Inst Biomech & Med Engn, Beijing, Peoples R China |
| Recommended Citation GB/T 7714 | Wang, Jin,Xie, Si-an,Li N,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.Rp_Au:Zhou, Jing |
| APA | Wang, Jin.,Xie, Si-an.,李宁.,Zhang, Tao.,Yao, Weijuan.,...&Zhou, Jing.(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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