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• W4206386045 endingPage "424" @default.
• W4206386045 startingPage "406" @default.
• W4206386045 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 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." @default.
• W4206386045 created "2022-01-26" @default.
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• W4206386045 date "2022-11-01" @default.
• W4206386045 modified "2023-10-17" @default.
• W4206386045 title "Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis" @default.
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• W4206386045 doi "https://doi.org/10.1016/j.bioactmat.2022.01.012" @default.
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• W4206386045 hasPublicationYear "2022" @default.
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