INTRODUCTION: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. METHODS: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. RESULTS: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. CONCLUSIONS: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 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.

The monocyte/macrophage infiltration plays critical roles in the development of atherosclerosis. Arterial stiffness is a cholesterol-independent risk factor for cardiovascular events. The regulation of arterial stiffness on biomechanics of macrophages and its underlying mechanism remains unclear. We prepared polyacrylamide gels with low and high stiffness that corresponded to healthy and diseased blood vessels, respectively. We found that macrophages cultured on stiff matrix had increased rigidity and migration ability compared to those on soft matrix. An actin capping protein, tropomodulin1 (Tmod1) was upregulated in macrophages by stiff matrix and in arteries with high stiffness. Further analyses showed that deficiency of Tmod1 in macrophages completely or partially prevented the changes in actin polymerization, cell adhesion and cell spreading induced by stiff matrix. Overexpression of Tmod1 in macrophages enhanced actin polymerization, cell adhesion and spreading on stiff matrix. Tmod1 was involved in the regulation of vinculin expression and formation of focal adhesion in macrophages on stiff matrix. Finally, the deficiency of Tmod1 in macrophages retarded the formation of atherosclerotic plaques in blood vessels with high matrix stiffness. The results suggest that Tmod1 was a key regulator in macrophage rigidity and migration on stiff substrate. The present work will help us to understand the biomechanical mechanisms for the development of atherosclerosis.

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.

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE −/− mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist–treated mice, blocking of short FSH surge by anti-FSHβ antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist–treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3β (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3β/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist–induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.

The cytoskeleton plays an important role in platinum resistance in ovarian cancer. Tropomodulin 3 (TMOD3) is critical in the development of many tumors, but its role in the drug resistance of ovarian cancer remains unexplored. By analyzing data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, this study compared TMOD3 expression in ovarian cancer and normal tissues, and examined the expression of TMOD3 after platinum treatment in platinum-sensitive and platinum- resistant ovarian cancers. The Kaplan-Meier method was used to assess the effect of TMOD3 on overall survival (OS) and progression-free survival (PFS) in ovarian cancer patients. microRNAs (miRNAs) targeting TMOD3 were predicted using TargetScan and analyzed using the TCGA database. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to determine the relationship between TMOD3 expression and immune infiltration. TMOD3 coexpression networks in ovarian cancer were explored using LinkedOmics, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and The Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics. The results showed that TMOD3 was highly expressed in ovarian cancer and was associated with the grading, staging, and metastasis of ovarian cancer. TMOD3 expression was significantly reduced in platinum-treated ovarian cancer cells and patients. However, TMOD3 expression was higher in platinum-resistant ovarian cancer cells and tissues compared to platinum- sensitive ones. Higher TMOD3 expression was significantly associated with lower OS and PFS in ovarian cancer patients treated with platinum-based chemotherapy. miRNA-mediated post-transcriptional regulation is likely responsible for high TMOD3 expression in ovarian cancer and platinum-resistant ovarian tissues. The expression of TMOD3 mRNA was associated with immune infiltration in ovarian cancer. These findings indicate that TMOD3 is highly expressed in ovarian cancer and is closely associated with platinum resistance and immune infiltration.

AbstractHigh‐magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)/ Yin Yang 1 (YY1)/ carnitine palmitoyltransferase 1b (CPT1B) signaling in coordinating VSMC mechanical activation by inhibiting fatty acid β‐oxidation. Metabolomic analysis showed that a 15%–1 Hz arterial cyclic stretch, compared to a 5%–1 Hz venous stretch, increased long‐chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%–1 Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid β‐oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. Overexpressing CPT1B or inhibiting cPLA2 reduced VSMC proliferation and migration in vein grafts, decreasing neointimal hyperplasia. This study uncovers a novel mechanism in lipid metabolic reprogramming in vein grafts, suggesting a new therapeutic target for vein graft hyperplasia.

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.

Background: Increasing evidence suggests that hemodynamic disturbed flow induces endothelial dysfunction via a complex biological process so-called endothelial to mesenchymal transition (EndoMT). Recently, DNA methyltransferases (DNMTs) was reported as a key molecular mediator to promote EndoMT. Our understanding of how DNMTs, particularly the maintenance DNMTs, DNMT1, coordinate EndoMT is still lacking. Methods: A parallel-plate flow apparatus and perfusion devices were used to apply fluid with endothelial protective pulsatile shear (PS, to mimic the laminar flow) or harmful oscillatory shear (OS, to mimic the disturbed flow) to cultured endothelial cells (ECs). Endothelial lineage tracing mice and conditional EC Dnmt1 knockout mice were subjected to a surgery of carotid partial ligation to generate the flow-accelerated atherogenesis models. Western blotting, quantitative RT-PCR, immunofluorescent staining, methylation-specific PCR, chromatin immunoprecipitation, endothelial functional assays, and assessments for neointimal formation and atherosclerosis were performed. Results: Inhibition of DNMTs with 5-aza-2'-deoxycytidine (5-Aza) suppressed the disturbed flow/OS-induced EndoMT, both in cultured cells and the endothelial lineage tracing mice. 5-Aza also ameliorated the downregulation of aldehyde dehydrogenases (ALDHs) and β-alanine biosynthesis caused by disturbed flow/OS. Knockdown of the ALDH family proteins, ALDH2, ALDH3A1, and ALDH6A1, showed an EndoMT-induction effect as OS. Supplementation of cells with the functional metabolites of β-alanine, carnosine and acetyl-CoA (acetate), reversed EndoMT, likely via inhibiting the phosphorylation of Smad2/3. Endothelial-specific knockout of Dnmt1 protected the vasculature from disturbed flow-induced remodeling and atherosclerosis. Conclusions: Endothelial DNMT1 acts as one of the key epigenetic factors to mediate the hemodynamically regulated EndoMT at least through repressing the expression of ALDH2, ALDH3A1, and ALDH6A1. Supplementation with carnosine and acetate may have a great potential in the prevention and treatment of atherosclerosis.

Mechanotransduction in endothelial cells is critical to maintain vascular homeostasis and can contribute to disease development, yet the molecules responsible for sensing flow remain largely unknown. Here, we demonstrate that the discoidin domain receptor 1 (DDR1) tyrosine kinase is a direct mechanosensor and is essential for connecting the force imposed by shear to the endothelial responses. We identify the flow-induced activation of endothelial DDR1 to be atherogenic. Shear force likely causes conformational changes of DDR1 ectodomain by unfolding its DS-like domain to expose the buried cysteine-287, whose exposure facilitates force-induced receptor oligomerization and phase separation. Upon shearing, DDR1 forms liquid-like biomolecular condensates and co-condenses with YWHAE, leading to nuclear translocation of YAP. Our findings establish a previously uncharacterized role of DDR1 in directly sensing flow, propose a conceptual framework for understanding upstream regulation of the YAP signaling, and offer a mechanism by which endothelial activation of DDR1 promotes atherosclerosis.

Dendritic cells (DCs) can mediate immune responses or immune tolerance depending on their immunophenotype and functional status. Remodeling of DCs’ immune functions can develop proper therapeutic regimens for different immune-mediated diseases. In the immunopathology of autoimmune diseases (ADs), activated DCs notably promote effector T-cell polarization and exacerbate the disease. Recent evidence indicates that metformin can attenuate the clinical symptoms of ADs due to its anti-inflammatory properties. Whether and how the therapeutic effects of metformin on ADs are associated with DCs remain unknown. In this study, metformin was added to a culture system of LPS-induced DC maturation. The results revealed that metformin shifted DC into a tolerant phenotype, resulting in reduced surface expression of MHC-II, costimulatory molecules and CCR7, decreased levels of proinflammatory cytokines (TNF-α and IFN-γ), increased level of IL-10, upregulated immunomodulatory molecules (ICOSL and PD-L) and an enhanced capacity to promote regulatory T-cell (T reg ) differentiation. Further results demonstrated that the anti-inflammatory effects of metformin in vivo were closely related to remodeling the immunophenotype of DCs. Mechanistically, metformin could mediate the metabolic reprogramming of DCs through FoxO3a signaling pathways, including disturbing the balance of fatty acid synthesis (FAS) and fatty acid oxidation (FAO), increasing glycolysis but inhibiting the tricarboxylic acid cycle (TAC) and pentose phosphate pathway (PPP), which resulted in the accumulation of fatty acids (FAs) and lactic acid, as well as low anabolism in DCs. Our findings indicated that metformin could induce tolerance in DCs by reprogramming their metabolic patterns and play anti-inflammatory roles in vitro and in vivo.

Abnormally high follicle-stimulating hormone (FSH) has been reported to associate with cardiovascular diseases in prostate cancer patients with specific androgen deprivation therapy and in menopausal women. All of the cardiovascular diseases were involved in atherosclerosis. However, the pathogenic mechanism of FSH-associated atherosclerosis remains uncertain. Apolipoprotein E-deficient mice were chosen to develop atherosclerosis, of which the plaques were analyzed with administration of short- and long-term FSH imitating androgen deprivation therapy-induced and menopausal FSH elevation. The study showed that short- and long-term exposure of FSH significantly accelerated atherosclerosis progression in apolipoprotein E-deficient mice, manifested as strikingly increased plaques in the aorta and its roots, increased macrophage content, reduced fibrin, and an enlarged necrotic core, suggesting a decrease in plaque stability. Furthermore, expression profiles from the Gene Expression Omnibus GSE21545 dataset revealed that macrophage inflammation was tightly associated with FSH-induced atherosclerotic progression. The human monocyte cell line THP-1 was induced by PMA and worked as a macrophage model to detect inflammatory factors and cellular functions. FSH remarkably promoted the expression of IL-1β in macrophages and strikingly increased the chemotactic migratory capacity of macrophages toward MCP-1, but the promigratory capacity of FSH was attenuated in foam cells. Overall, we revealed that FSH significantly promoted the inflammatory response and migration of macrophages, thereby provoking atherosclerosis development.

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 LATS1 (large tumor suppressor 1), 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.

血管平滑肌细胞(vascular smooth muscle cell,VSMC)在血管生理功能维持和动脉粥样硬化、动脉硬化与钙化、动脉瘤与夹层等血管疾病发生、发展、转归过程中发挥重要作用.因其表型的高度可塑性,VSMC可对血液动力学因素、管壁细胞外基质刚度和拓扑等多种机械力刺激予以应答,通过表型转换而参与血管稳态和重塑调控.本文阐述了 VSMC感知、转导和响应其所处力学微环境的关键受体和信号转导途径,并基于作者研究团队近年来的工作,重点介绍了酪氨酸激酶受体型机械力信号受体和核机械力信号受体等在机械力感知过程中的作用和机制.

Decreased vascular compliance of the large arteries as indicated by increased pulse wave velocity is shown to be associated with atherosclerosis and the related cardiovascular events. The positive correlation between arterial stiffening and disease progression derives a hypothesis that softening the arterial wall may protect against atherosclerosis, despite that the mechanisms controlling the cellular pathological changes in disease progression remain unknown. Here, we established a mechanical-property-based screening to look for compounds alleviating the arterial wall stiffness through their actions on the interaction between vascular smooth muscle cells (VSMCs) and the wall extracellular matrix (ECM). We found that echinatin, a chalcone preferentially accumulated in roots and rhizomes of licorice (Glycyrrhiza inflata), reduced the stiffness of ECM surrounding cultured VSMCs. We examined the potential beneficial effects of echinatin on mitigating arterial stiffening and atherosclerosis, and explored the mechanistic basis by which the compound exert the effects. Administration of echinatin in mice fed on an adenine diet and in hyperlipidemia mice subjected to 5/6 nephrectomy mitigated arterial stiffening and atherosclerosis. Mechanistic insights were gained from the RNA-sequencing results showing that echinatin upregulated the expression of glutamate cysteine ligases (GCLs), both the catalytic (GCLC) and modulatory (GCLM) subunits. Further study indicated that upregulation of GCLC/GCLM in VSMCs by echinatin maintains the homeostasis of glutathione (GSH) metabolism; adequate availability of GSH is critical for counteracting arterial stiffening. As a consequence of regulating the GSH synthesis, echinatin inhibits ferroptosis and matrix remodeling that being considered two contributors of arterial stiffening and atherosclerosis. These data demonstrate a pivotal role of GSH dysregulation in damaging the proper VSMC-ECM interaction and uncover a beneficial activity of echinatin in preventing vascular diseases.

Disturbed blood flow induces endothelial pro-inflammatory responses that promote atherogenesis. Nanoparticle-based therapeutics aimed at treating endothelial inflammation in vasculature where disturbed flow occurs may provide a promising avenue to prevent atherosclerosis. By using a vertical-step flow apparatus and a microfluidic chip of vascular stenosis, herein, it is found that the disk-shaped versus the spherical nanoparticles exhibit preferential margination (localization and adhesion) to the regions with the pro-atherogenic disturbed flow. By employing a mouse model of carotid partial ligation, superior targeting and higher accumulation of the disk-shaped particles are also demonstrated within disturbed flow areas than that of the spherical particles. In hyperlipidemia mice, administration of disk-shaped particles loaded with hypomethylating agent decitabine (DAC) displays greater anti-inflammatory and anti-atherosclerotic effects compared with that of the spherical counterparts and exhibits reduced toxicity than "naked" DAC. The findings suggest that shaping nanoparticles to disk is an effective strategy for promoting their delivery to atheroprone endothelia.

Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.

Vascular smooth muscle cells (SMCs) can adapt to changes in cellular geometric cues; however, the underlying mechanisms remain elusive. Using 2D micropatterned substrates to engineer cell geometry, it is found that in comparison with an elongated geometry, a square-shaped geometry causes the nuclear-to-cytoplasmic redistribution of DNA methyltransferase 1 (DNMT1), hypermethylation of mitochondrial DNA (mtDNA), repression of mtDNA gene transcription, and impairment of mitochondrial function. Using irregularly arranged versus circumferentially aligned vascular grafts to control cell geometry in 3D growth, it is demonstrated that cell geometry, mtDNA methylation, and vessel contractility are closely related. DNMT1 redistribution is found to be dependent on the phosphoinositide 3-kinase and protein kinase B (AKT) signaling pathways. Cell elongation activates cytosolic phospholipase A2, a nuclear mechanosensor that, when inhibited, hinders AKT phosphorylation, DNMT1 nuclear accumulation, and energy production. The findings of this study provide insights into the effects of cell geometry on SMC function and its potential implications in the optimization of vascular grafts.