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

Wang, Jin; Xie, Sian; Li, Ning; Zhang, Tao; Yao, Weijuan; Zhao, Hang; Pang, Wei; Han, Lili; Liu, Jiayu; Zhou, Jing

doi:10.1016/j.bioactmat.2022.01.012

Cited by 21 publications

(24 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, substrate stiffness promoted the colocalization of DDR1 and Rab5A (Ras-related protein Rab-5A), an early endosome marker that indicate receptor internalization, and DDR1-IN-1 attenuated their colocalization (Figure S4C), in consistent with previous report. 24 Collectively, these results demonstrate that activation of DDR1 is required for the stiffness-initiated YAP signaling.…”

Section: Resultsmentioning

confidence: 80%

“…In addition, substrate stiffness promoted the S4C), in consistent with previous report. 24 Collectively, these results demonstrate that activation of DDR1 is required for the stiffness-initiated YAP signaling.…”

Section: Ddr1 Is Required For Stiffness-induced Yap Activationmentioning

confidence: 80%

“…[24][25][26] Nonetheless, the effector molecules downstream of DDR1 as well as the functional outcomes of DDR1 activation remain ambiguous. Although previous reports have indicated that systemic depletion of DDR1 in mice compromises vascular calcification in diabetes and ameliorates atherosclerosis in mice fed on an atherogenic diet, 30,59 and that systemic administration of DDR1-IN-1 in mice counteracts the adenine diet-induced arterial stiffening, a study reported by us, 24 investigations on animals with VSMC-specific depletion of DDR1 may provide more insights to the roles of DDR1 in vascular diseases. Here we identified that the VSMC-specific depletion of DDR1 leads to the attenuation of arterial stiffening in a chronic kidney failure mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…15 The DDR1 (discoidin domain receptor 1) is capable of implementing mechanosensing in VSMCs. [24][25][26] As a collagen-binding receptor tyrosine kinase, it undergoes tyrosine autophosphorylation upon activation by ECM…”

Section: Original Researchmentioning

confidence: 99%

“…The DDR1 (discoidin domain receptor 1) is capable of implementing mechanosensing in VSMCs. 24–26 As a collagen-binding receptor tyrosine kinase, it undergoes tyrosine autophosphorylation upon activation by ECM stiffness. 27 Mechanical activation of DDR1 in VSMCs causes receptor oligomerization, clustering and internalization, and activation of the downstream signaling in the presence or absence of collagen binding.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening

Liu

Wang

Liu

et al. 2023

Circulation Research

Self Cite

View full text Add to dashboard Cite

BACKGROUND: The Hippo-YAP (yes-associated protein) signaling pathway is modulated in response to various environmental cues. Activation of YAP in vascular smooth muscle cells conveys the extracellular matrix stiffness-induced changes in vascular smooth muscle cells phenotype and behavior. Recent studies have established a mechanoreceptive role of receptor tyrosine kinase DDR1 (discoidin domain receptor 1) in vascular smooth muscle cells. METHODS: We conduced 5/6 nephrectomy in vascular smooth muscle cells-specific Ddr1-knockout mice, accompanied by pharmacological inhibition of the Hippo pathway kinase large tumor suppressor 1 (LATS1), to investigate DDR1 in YAP activation. We utilized polyacrylamide gels of varying stiffness or the DDR1 ligand, type I collagen, to stimulate the cells. We employed multiple molecular biological techniques to explore the role of DDR1 in controlling the Hippo pathway and to determine the mechanistic basis by which DDR1 exerts this effect. RESULTS: We identified the requirement for DDR1 in stiffness/collagen-induced YAP activation. We uncovered that DDR1 underwent stiffness/collagen binding-stimulated liquid-liquid phase separation and co-condensed with LATS1 to inactivate LATS1. Mutagenesis experiments revealed that the transmembrane domain is responsible for DDR1 droplet formation. Purified DDR1 N-terminal and transmembrane domain was sufficient to drive its reversible condensation. Depletion of the DDR1 C-terminus led to failure in co-condensation with LATS1. Interaction between the DDR1 C-terminus and LATS1 competitively inhibited binding of MOB1 (Mps one binder 1) to LATS1 and thus the subsequent phosphorylation of LATS1. Introduction of the single-point mutants, histidine-745-proline and histidine-902-proline, to DDR1 on the C-terminus abolished the co-condensation. In mouse models, YAP activity was positively correlated with collagen I expression and arterial stiffness. LATS1 inhibition reactivated the YAP signaling in Ddr1-deficient vessels and abrogated the arterial softening effect of Ddr1 deficiency. CONCLUSIONS: These findings identify DDR1 as a mediator of YAP activation by mechanical and chemical stimuli and demonstrate that DDR1 regulates LATS1 phosphorylation in an liquid-liquid phase separation-dependent manner.

show abstract

Section: Resultsmentioning

confidence: 80%

Section: Ddr1 Is Required For Stiffness-induced Yap Activationmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Original Researchmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening

Liu

Wang

Liu

et al. 2023

Circulation Research

Self Cite

View full text Add to dashboard Cite

show abstract

Challenges and Future Directions

Suhag,

Kaushik,

Taxak

2024

Biomedical Materials for Multi-Functional Applications

View full text Add to dashboard Cite

Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis

Qin,

Ma,

Huang

et al. 2024

Curr Atheroscler Rep

View full text Add to dashboard Cite

Purpose of Review The primary objective of this review is to explore the pathophysiological roles and clinical implications of lipoprotein(a) [Lp(a)] in the context of atherosclerotic cardiovascular disease (ASCVD). We seek to understand how Lp(a) contributes to inflammation and arteriosclerosis, aiming to provide new insights into the mechanisms of ASCVD progression. Recent Findings Recent research highlights Lp(a) as an independent risk factor for ASCVD. Studies show that Lp(a) not only promotes the inflammatory processes but also interacts with various cellular components, leading to endothelial dysfunction and smooth muscle cell proliferation. The dual role of Lp(a) in both instigating and, under certain conditions, mitigating inflammation is particularly noteworthy. Summary This review finds that Lp(a) plays a complex role in the development of ASCVD through its involvement in inflammatory pathways. The interplay between Lp(a) levels and inflammatory responses highlights its potential as a target for therapeutic intervention. These insights could pave the way for novel approaches in managing and preventing ASCVD, urging further investigation into Lp(a) as a therapeutic target.

show abstract

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

Cited by 21 publications

References 66 publications

Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening

Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening

Challenges and Future Directions

Lipoprotein (a)-Related Inflammatory Imbalance: A Novel Horizon for the Development of Atherosclerosis

Contact Info

Product

Resources

About