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

作     者：Jin Wang Si-an Xie Ning Li Tao Zhang Weijuan Yao Hucheng Zhao Wei Pang Lili Han Jiayu Liu Jing Zhou 

作者机构：Department of Physiology and PathophysiologySchool of Basic Medical SciencesHemorheology CenterSchool of Basic Medical SciencesPeking UniversityBeijingPR China Key Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijingPR China National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesBeijing Key Laboratory of Cardiovascular Receptors ResearchPeking UniversityBeijingPR China Department of GastroenterologyBeijing Friendship HospitalCapital Medical UniversityNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive DiseaseBeijingPR China Center for Biomechanics and BioengineeringKey Laboratory of Microgravity(National Microgravity Laboratory)And Beijing Key Laboratory of Engineered Construction and MechanobiologyInstitute of MechanicsChinese Academy of SciencesBeijingPR China School of Engineering SciencesUniversity of Chinese Academy of SciencesBeijingPR China Department of Vascular SurgeryPeking University People’s HospitalBeijingPR China Institute of Biomechanics and Medical EngineeringSchool of Aerospace EngineeringTsinghua UniversityBeijingPR China 

出 版 物：《Bioactive Materials》 (生物活性材料（英文）)

年 卷 期：2022年第7卷第11期

页      面：406-424页

核心收录：

学科分类：0831[工学-生物医学工程（可授工学、理学、医学学位）] 1002[医学-临床医学] 08[工学] 0805[工学-材料科学与工程（可授工学、理学学位）] 10[医学] 

基　　金：This work was funded by the National Natural Science Foundation of the China(#91949112,#81974052,#81921001,#91939302,and#31870930) Peking University Health Science Center,the Plan for Strengthening the Basic Research(#BMU2020JC002). 

主　　题：Matrix stiffness Inflammation DDR1 DNMT1 Mechanotransduction 

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 microenvironments 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.