Weijuan Yao

BACKGROUND: Chronic kidney disease (CKD) increases cardiovascular risk and is linked to arterial stiffening and atherosclerosis. How stiffness promotes atherogenesis remains unclear. DDR1 (discoidin domain receptor 1), a mechanosensory tyrosine kinase receptor, has been implicated in force-regulated arterial remodeling. We investigated whether DDR1-mediated mechanosensation links arterial stiffness to vascular smooth muscle cell (SMC)-endothelial paracrine communication in CKD-related atherosclerosis. METHODS: Single-cell RNA sequencing, secretome proteomics, and bulk RNA sequencing were integrated with stiffness-controlled models, endothelial assays, and a CKD-hyperlipidemia mouse model. SMC-specific Ddr1 deletion and a DDR1 dephosphorylation-targeting chimera (DEPTAC) were evaluated in vivo. Plasma TSP-1 (thrombospondin-1) levels were quantified in a CKD clinical cohort and analyzed in relation to renal function and atherosclerosis severity. RESULTS: CKD-associated vascular stiffening coincided with SMC phenotypic switching and enhanced THBS signaling. Multiomics integration identified THBS1 as a stiffness-induced SMC secretory effector. Stiff matrices increased SMC THBS1 secretion, promoting endothelial proliferation, migration, and leukocyte adhesion; these effects were attenuated by THBS1 knockdown. DDR1 coupled matrix stiffness cues to THBS1 expression by regulating its transcription via a tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon-FOXO3 (forkhead box O3) axis. Vascular SMC-specific Ddr1 deletion reduced aortic THBS1 levels, vascular stiffening, and atherosclerotic burden. DEPTAC suppressed aberrant DDR1 phosphorylation, reduced THBS1, and ameliorated vascular stiffening and atherosclerosis. Plasma THBS1 increased with CKD severity and correlated with atherosclerosis. CONCLUSIONS: DDR1-dependent mechanosensing in SMCs drives stiffness-induced paracrine signaling to endothelium via THBS1, promoting CKD-accelerated atherosclerosis. Targeting mechanical DDR1 activation may be therapeutic.

Endothelial cell (EC) mechanosensing is essential for vascular homeostasis and atherosclerosis development, though the influence of blood flow patterns on EC signaling is not fully understood. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, acts as a mechanosensor linking shear force to endothelial responses. Atheroprotective laminar shear flow induces rapid, transient DDR1 activation and condensation through liquid-liquid phase separation without harmful effects, while atherogenic shear causes delayed, sustained condensation, leading to Yes-associated protein (YAP) activation and downstream pathological signaling. We show that heat shock protein 27 (HSP27) regulates shear-dependent DDR1 condensation and phase transition. Specifically, the interaction between DDR1 and HSP27, mediated by their respective domains, is crucial for DDR1 condensate disassembly. Atherogenic shear, unlike atheroprotective shear, triggers prolonged DDR1-mediated HSP27 phosphorylation, promoting DDR1 gel transition and activating YAP signaling. The DDR1-HSP27 axis is key in endothelial YAP activation and atherogenesis in vivo. Targeting this pathway may offer therapeutic potential for preventing endothelial dysfunction and atherosclerosis.

Introduction: Ischemic heart disease (IHD) remains a leading global health challenge, with smoking identified as a key modifiable risk factor. China, with its high smoking prevalence and aging population, faces a growing burden of smoking-related IHD. This study evaluates the disease burden of...

Smoking is a major risk factor for aortic aneurysm (AA). This cross-sectional study used Global Burden of Disease (GBD) data to examine trends in smoking-related AA and project future trends. We conducted a secondary analysis on the GBD 2021 dataset. Data on mortality, disability-adjusted life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) associated with AA attributable to smoking from GBD. The estimated annual percentage change (EAPC) was employed to assess burden trends from 1990 to 2021. The autoregressive integrated sliding average (ARIMA) model was utilized to project disease trends from 2022 to 2036. Decomposition analysis and frontier analysis were employed to comprehensively examine the data. Globally in 2021, there were 47538 deaths (95% UI: 39480–56008) from smoking-attributable AA, with an ASMR of 0.56 per 100000 (95% UI: 0.46–0.66) and 1157488 DALYs (95% UI: 989966–1325831). The ASMR showed a decreasing trend from 1990 to 2021 (EAPC= -2.17; 95% CI: -2.30 – -2.04). However, there were significant differences between regions, with the burden of deaths in high sociodemographic index (SDI) areas accounting for 40.3% of the global total, while ASMR in low-middle SDI areas rose (EAPC=0.99; 95% CI: 0.94–1.03). The point estimates for ASMR and ASDR were consistently greater in males compared to females throughout the study period. Projections indicate a continued global decline in ASMR and ASDR over the next 15 years, but the burden would gradually rise in Central Asia, East Asia, and South Asia. Smoking remains a significant preventable risk factor for AA, with substantial sex and regional disparities. Targeted public health strategies are urgently needed to address rising burdens in specific regions and reduce health inequalities.

Endothelial regeneration is critical for maintaining vascular homeostasis and inhibiting neointimal formation during vascular repair following injury. While extracellular matrix (ECM) stiffness of the vascular wall is known to influence vascular endothelial cell (EC) behavior, its role in post-injury endothelial regeneration remains poorly understood. Here, we demonstrate a dynamic change in vascular wall stiffness post-injury, with an initial transient decrease within 5 days, followed by a subsequent increase. Our findings reveal that ECM stiffness enhances the interaction between Apurinic/apyrimidinic endonuclease 1 (APEX1) and the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Their interaction promotes ROCK2-dependent phosphorylation of STAT3, facilitating its nuclear translocation and activation. Activated STAT3 drives EC proliferation, migration, and re-establishment of endothelial junctions. Additionally, we identify that STAT3 forms cytoplasmic condensates that impede its activation. ECM stiffening or APEX1 overexpression suppresses these condensates, enabling STAT3 activation. This study elucidates a novel mechanotransduction mechanism by which ECM stiffness regulates EC function through the APEX1-STAT3 signaling axis, offering insights into the coordination of endothelial regeneration during vascular repair.

The excessive inflammation caused by the prolonged activation of Toll-like receptor 4 (TLR4) and its downstream signaling pathways leads to sepsis. CD14-mediated endocytosis of TLR4 is the key step to control the amount of TLR4 on cell membrane and the activity of downstream pathways. The actin cytoskeleton is necessary for receptor-mediated endocytosis, but its role in TLR4 endocytosis remains elusive. Here we show that Tropomodulin 1 (Tmod1), an actin capping protein, inhibited lipopolysaccharide (LPS)-induced TLR4 endocytosis and intracellular trafficking in macrophages. Thus it resulted in increased surface TLR4 and the upregulation of myeloid differentiation factor 88 (MyD88)-dependent pathway and the downregulation of TIR domain-containing adaptor-inducing interferon-β (TRIF)-dependent pathway, leading to the enhanced secretion of inflammatory cytokines, such as TNF-α and IL-6, and the reduced secretion of cytokines, such as IFN-β. Macrophages deficient with Tmod1 relieved the inflammatory response in LPS-induced acute lung injury mouse model. Mechanistically, Tmod1 negatively regulated LPS-induced TLR4 endocytosis and inflammatory response through modulating the activity of CD14/Syk/PLCγ2/IP3/Ca²⁺ signaling pathway, the reorganization of actin cytoskeleton, and the membrane tension. Therefore, Tmod1 is a key regulator of inflammatory response and immune functions in macrophages and may be a potential target for the treatment of excessive inflammation and sepsis.

The cytoskeleton plays an important role in platinum resistance in ovarian cancer. Tropomodulin 3 (TMOD3) is critical in the development of many tumors, ... Jove