Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"COPI Coatomer Regulates Several Steps of HDL Metabolism.","authors":"Grigorios Panteloglou, Paolo Zanoni, Christopher S Law, Brian Woods, Alaa Othman, Mustafa Yalcinkaya, Simon F Norrelykke, Andrzej J Rzepiela, Szymon Stoma, Michael Stebler, Anja Kerksiek, Michele Visentin, Marieke Smit, Justina Clarinda Wolters, Sofia Kakava, Anton Potapenko, Eveline Schlumpf, Silvija Radosavljevic, Stephanie Häusler, Marta Futema, Nawar Dalila, Anne Tybjaerg-Hansen, Steve E Humphries, Jan Albert Kuivenhoven, Bart van de Sluis, Dieter Lütjohann, Roger Meier, Jérôme Robert, Janet Chou, Raif S Geha, Anthony K Shum, Lucia Rohrer, Arnold von Eckardstein","doi":"10.1161/ATVBAHA.126.324616","DOIUrl":"10.1161/ATVBAHA.126.324616","url":null,"abstract":"<p><strong>Background: </strong>Reverse cholesterol transport by HDLs (high-density lipoproteins) is considered an antiatherogenic metabolic pathway. Hepatocytes are the main contributors to the efficacy of this pathway by the production of apoA-I (apolipoprotein A1) and its lipidation by ABCA1 (ATP-binding cassette transporter A1), selective uptake of cholesterol via SR-BI (scavenger receptor class B type 1), and uptake of entire HDL particles. The molecular determinants of the latter step are not well understood.</p><p><strong>Methods: </strong>We performed a genome-wide RNA interference screen for genes limiting the uptake of HDL fluorescently labeled at its protein moiety into Huh-7 hepatocarcinoma cells. Top hit genes were validated by targeted in vitro experiments and the analysis of associations between their variants and HDL-C (HDL-cholesterol) levels in the databases of the Global Lipids Genetics Consortium and the UK Biobank, as well as inborn errors of metabolism and their respective mouse models.</p><p><strong>Results: </strong>The knockdown of 128 genes significantly inhibited HDL uptake. Six of them encode components of the COPI (coat protein I) coatomer, namely, <i>COPA</i>, <i>COPB1</i>, <i>COPB2</i>, <i>COPG1</i>, <i>ARCN1</i>, and <i>COPZ1</i>. Knocking down any of them decreased the uptake of both fluorescently labeled proteins and lipids of HDL, the cell surface abundance of SR-BI, and <i>APOA1</i> expression and apoA-I secretion but increased the cell surface abundance of ABCA1. Common single-nucleotide polymorphisms of <i>ARCN1</i> and <i>COPB1</i> were associated with significantly higher HDL-C levels in the population, while rare <i>COPA</i> and <i>COPG1</i> variants causing immunopathies were associated with rather lower levels of HDL-C in both affected patients and the corresponding genetically modified mice.</p><p><strong>Conclusions: </strong>In hepatocytes, the COPI coatomer regulates HDL holoparticle uptake, selective lipid uptake, apoA-I secretion, and ABCA1 expression, and thereby, it influences plasma levels of HDL-C.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324616"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13475002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SEPTIN7 Deficiency Disrupts Endothelial Integrity and Causes Myxomatous Valve Disease in Juvenile Mice.","authors":"Yuan Fang, Hongyu Su, Jinling Dong, Weihao Xue, Chengrong Yan, Shaozhou Ma, Lihua Yang, Xin Min, Benheng Qian, Baochang Lai, Rui Xi, Donghong Zhang, Yanmin Zhang, Bin Zhou, Lei Shi, Lianpin Wu, Feng Xiao, Yidong Wang","doi":"10.1161/ATVBAHA.126.325078","DOIUrl":"10.1161/ATVBAHA.126.325078","url":null,"abstract":"<p><strong>Background: </strong>Myxomatous valve degeneration is a major contributor to adult-onset valvular disease, with congenital valve abnormalities being a predisposing factor. However, the molecular networks that govern heart valve development, particularly postnatal valve maturation, remain poorly understood. This study was designed to investigate the role of GTP‑binding SEPTIN proteins in heart valve formation.</p><p><strong>Methods: </strong>We generated endocardial lineage-specific conditional knockout mouse models targeting <i>Septin2</i>, <i>Septin7</i>, or <i>Septin9</i>. Cardiac phenotypes were assessed using histopathology, immunohistochemistry, and molecular analyses.</p><p><strong>Results: </strong>Mice lacking <i>Septin2</i> or <i>Septin9</i> developed normally without detectable abnormalities. In contrast, <i>Septin7</i> mutant mice exhibited juvenile lethality due to congestive heart failure caused by severe aortic stenosis. Although valve structure appeared normal at birth, <i>Septin7</i> mutants progressively developed myxomatous degeneration, characterized by leaflet thickening, extracellular matrix disorganization, and inflammatory infiltration. Loss of <i>Septin7</i> disrupted valvular endothelial integrity, with increased intercellular gaps and reduced expression of cell-cell junction proteins. Mechanistically, <i>Septin7</i> ablation inhibited endothelial cell proliferation, most likely through upregulation of the cell cycle inhibitor p21.</p><p><strong>Conclusions: </strong>Altogether, our findings identify a previously unrecognized role of SEPTIN7 in postnatal heart valve maturation and homeostasis, wherein it safeguards endothelial integrity. This discovery provides critical mechanistic insights into the pathogenesis of pediatric myxomatous valve disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325078"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disarming FcγRIIA: Separating Immunothrombosis From Protective Immunity.","authors":"Pierre H Mangin, Elizabeth E Gardiner","doi":"10.1161/ATVBAHA.126.325504","DOIUrl":"10.1161/ATVBAHA.126.325504","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325504"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monovalent Anti-FcγRIIA Antibody Blocks Immune-Mediated Thrombocytopenia and Thrombosis With Minimal Adverse Side Effects in Mice.","authors":"Hem K Tamang, Jennifer Yueng, Susan Chyou, Brian R Curtis, Donald R Lynch, Tamer I Mahmoud, Benjamin E Tourdot","doi":"10.1161/ATVBAHA.126.324890","DOIUrl":"10.1161/ATVBAHA.126.324890","url":null,"abstract":"<p><strong>Background: </strong>Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder caused by antibodies to PF4 (platelet factor 4)-heparin complexes that activate FcγRIIA (Fc gamma receptor IIA). Existing HIT treatments inadequately suppress antibody-mediated cellular activation, leading to suboptimal thrombosis protection. FcγRIIA antibodies prevent HIT IgG (immunoglobulin G)-mediated cellular activation in vitro and thrombus formation in murine models, making them a potential therapeutic strategy for HIT. However, a clinical trial of an FcγRIIA antibody was terminated due to tolerability issues, emphasizing the need for safer alternatives. We hypothesized that a monovalent anti-FcγRIIA antibody could prevent HIT-associated thrombosis without eliciting adverse events.</p><p><strong>Methods: </strong>We engineered a monovalent, scFv (single-chain variable fragment; sc9600) targeting FcγRIIA and evaluated its activity using complementary in vitro and in vivo approaches. In vitro, studies in human platelets and whole blood assessed receptor binding, selectivity, and inhibition of HIT immune complex-mediated cellular activation. To extend these findings, in vivo efficacy and safety were evaluated in mice expressing human Fc receptors, including models of immune thrombocytopenia and thrombosis.</p><p><strong>Results: </strong>sc9600 bound FcγRIIA on human platelets with nanomolar affinity, rapidly achieved surface occupancy, and did not promote FcγRIIA internalization. sc9600 potently inhibited IgG-dependent platelet activation, including patient with HIT plasma, while preserving platelet responses to collagen and thrombin. Compared with clinically available drugs (Bruton tyrosine kinase/spleen tyrosine kinase inhibitors and P2Y₁₂ antagonists), sc9600 showed greater selectivity for IgG-driven platelet activation with no impact on in vitro thrombus formation. In whole blood, sc9600 reduced HIT-immune complex-mediated leukocyte activation, including monocyte tissue factor expression and neutrophil extracellular trap formation, without impairing phagocytosis. In vivo, sc9600 conjugated to mouse serum albumin was well tolerated, did not prolong bleeding, and protected against FcγRIIA-dependent immune thrombocytopenia and thrombosis, whereas full-length 9600 retained residual biologic activity associated with platelet clearance.</p><p><strong>Conclusions: </strong>These findings suggest that single-chain or effector-null anti-FcγRIIA blocking antibodies are a promising therapeutic strategy to treat HIT while minimally affecting hemostasis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324890"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Twist1</i> Promotes Endothelial Phenotypic Transition and Unstable Plaque Phenotype During Atherosclerosis.","authors":"Danielle C M Dy, Thiel Lehman, Benjamin D Henson, Jeeya Shah, Jessica Lin, Tiffany Riascos, Robert Wirka","doi":"10.1161/ATVBAHA.126.324428","DOIUrl":"10.1161/ATVBAHA.126.324428","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive investigation of endothelial cell (EC) dysfunction during atherosclerosis with single-cell omics has resulted in the proposal that ECs undergo multiple alternative cell fate decisions during disease, but lack of lineage tracing or spatial localization complicates interpretation of these data. <i>TWIST1</i>, a causal gene for multiple atherosclerotic vascular diseases, is activated with low shear stress in ECs, and EC-<i>Twist1</i> knockout results in reduced atherosclerosis. However, it remains unclear how <i>Twist1</i> affects EC phenotype and plaque biology.</p><p><strong>Methods: </strong>We performed EC lineage tracing, in situ analysis, and scRNA-Seq (single-cell RNA-sequencing) in <i>ApoE</i>^<i>-/-</i> mice, both before disease and after 16 weeks of high-fat diet. We also performed these studies with 2 mouse models of EC <i>Twist1</i> deletion. We overexpressed <i>TWIST1</i> in human coronary artery ECs exposed to different flow conditions, followed by bulk RNA-seq. Human scRNA-Seq data were used to validate key findings in the mouse model.</p><p><strong>Results: </strong>We found that EC phenotypic modulation during atherosclerosis is characterized by both proinflammatory and endothelial-to-mesenchymal transition gene programs, occurring simultaneously along a single-cell fate transition. Human scRNA-Seq data validated a similar endothelial-to-mesenchymal transition during disease. We found that the commonly used <i>Twist1</i> conditional allele is hypomorphic, leading to reduced <i>Twist1</i> expression in multiple cell types. Using a mouse model of EC-specific <i>Twist1</i> deletion, we found reduced EC phenotypic modulation, decreased lesion size, and a more stable lesion phenotype. Integration of <i>TWIST1</i> overexpression in human coronary artery ECs with the mouse scRNA-seq data identified specific <i>TWIST1</i>-induced targets including CXCL12 and E-selectin during EC phenotypic modulation.</p><p><strong>Conclusions: </strong>Our study revealed important aspects of EC phenotypic modulation during atherosclerosis, unifying disparate observations in the field. We identified key cellular and molecular mechanisms underlying a top risk locus for multiple vascular diseases, highlighting the promotion of inflammatory endothelial-to-mesenchymal transition by <i>TWIST1</i> as a key driver of disease risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324428"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Time of Day as a Biological Variable in Cardiovascular and Kidney Disease Research: A Scientific Statement From the American Heart Association.","authors":"David M Pollock, Tami A Martino, Kristen L Knutson, Satchidananda Panda, Amandine Chaix, Ketema Paul, Daichi Shimbo, Michelle L Gumz","doi":"10.1161/ATV.0000000000000198","DOIUrl":"10.1161/ATV.0000000000000198","url":null,"abstract":"<p><p>Lifestyle behaviors such as diet, physical activity, and sleep play a prominent role at every stage of cardiometabolic disease. These behaviors follow daily, circadian rhythms in humans. These endogenous biological rhythms are controlled by an autonomous molecular clock present in every cell of the body. This presents a translational mismatch wherein in-clinic human procedures are typically performed on awake, active individuals in a fed state, whereas in-laboratory procedures on rodents are often conducted in the daytime during their inactive, rest phase, when they are minimally motivated to eat. This American Heart Association scientific statement is intended to raise awareness that time of day is a biological variable that must be considered as a key modulatory factor in all facets of biomedical research from basic to clinical science. The entirety of the cardiovascular and renal systems function in a circadian fashion, making the time of day critically important in understanding basic and clinical research. This daily variability ranges from gene expression to functional outputs and everything in between. Here, we provide rationale for why time of day needs to be considered in various aspects of experimental design and interpretation in research and provide what we believe are useful suggestions to strengthen the rigor and utility of cardiometabolic and kidney research.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e000198"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying Pulmonary Endothelial Cell Zonation From Single-Cell Transcriptomics.","authors":"Stefanie N Sveiven, Carsten Knutsen, Fabio Zanini, David N Cornfield, Cristina M Alvira","doi":"10.1161/ATVBAHA.126.324377","DOIUrl":"10.1161/ATVBAHA.126.324377","url":null,"abstract":"<p><strong>Background: </strong>The lung vasculature is comprised of a series of branching vessels extending from the main pulmonary artery to the alveolar capillaries, then back to the pulmonary veins. Lung endothelial cells (EC) exist along this continuum, exposed to gradients of shear stress, oxygen tension, and pressure. Single-cell RNA sequencing has identified lung EC subsets, but many aspects of the vascular continuum, including vessel size and capillary polarity, remain undefined from transcriptomic data.</p><p><strong>Methods: </strong>We created an EC-enriched single-cell RNA sequencing data set from the P3 mouse lung. Using diffusion pseudotime, we developed an analytical framework to delineate transcriptomic gradients and assign vessel-size scores to categorize individual EC along the vascular continuum. We validated size-related gene expression patterns with fluorescence in situ hybridization and tested the application of this framework to transcriptomic data sets derived from diverse species and developmental stages.</p><p><strong>Results: </strong>We categorized capillary 1, arterial, and venous EC along 2 gradients: arterio-venous zonation and vessel size, distinguishing large arteries from arterioles, large veins from venules, and revealing arterio-venous polarity within the capillaries. Our data recapitulated previously established zonally defined cell signaling axes, identified unique cellular communication patterns in large versus small vessels, and localized injury-induced venous EC proliferation to vessels of specific size. This analytical framework was successfully applied to categorize lung EC by size in several published mouse and human data sets across different stages of lung development.</p><p><strong>Conclusions: </strong>Our findings provide a new approach to analyze transcriptional data to map EC along the pulmonary vascular tree, enabling the assignment of individual EC to vessels of a relative size. This framework allows the inference of spatial information from gene expression alone, thus providing novel mechanistic insights into pulmonary vascular diseases affecting specific vascular segments.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324377"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspirin Inhibits the cGAS-STING Signaling Pathway to Ameliorate the Development of Aortic Aneurysm and Dissection.","authors":"Yi-Fan Zeng, Qiu-Guo Wang, Zhen Qi, Jing-Yu Li, Zhi-Cheng Duan, Wen-Jing Zeng, Ye-Rong Hu, Ling Tan, Hao Tang","doi":"10.1161/ATVBAHA.126.324930","DOIUrl":"10.1161/ATVBAHA.126.324930","url":null,"abstract":"<p><strong>Background: </strong>Aortic aneurysm and dissection (AAD) is a life-threatening vascular disease that currently lacks effective pharmacological therapies. Clinical evidences suggest that aspirin may exert a protective effect on AAD, but the underlying molecular mechanism is still unclear at present.</p><p><strong>Methods: </strong>Three mouse animal models of AAD and H₂O₂-induced ferroptosis model in human aortic vascular smooth muscle cells (HAVSMCs) were established. On this basis, RNA sequencing was performed to investigate potential molecular mechanisms, and further experiments were conducted using STING (stimulator of interferon genes) agonist to confirm the mechanisms.</p><p><strong>Results: </strong>Aspirin was found to ameliorate the progression of AAD in the β-aminopropionitrile and CaPO₄ mouse models. Interestingly, aspirin reduced mortality in mice but did not reduce the incidence of AAD in the β-aminopropionitrile + angiotensin II model. Furthermore, aspirin inhibited H₂O₂-induced ferroptosis in HAVSMCs and suppressed activation of cGAS (cyclic GMP-AMP synthase)-STING signaling pathway. Activation of STING with STING agonist markedly increased STING, TBK1 (TANK-binding kinase 1), and IRF3 (interferon regulatory factor 3) phosphorylation and abolished the protective effect of aspirin against H₂O₂-induced ferroptosis in HAVSMCs. Western blot and immunofluorescence results indicated significant activation of the cGAS-STING signaling pathway following treatment with STING agonist. Coimmunoprecipitation analysis revealed that cGAS acetylation was considerably enhanced in HAVSMCs after aspirin treatment. Additionally, administration of aspirin and dimeric amidobenzimidazole compound 3 showed that dimeric amidobenzimidazole abolished the protective effect of aspirin in the CaPO₄ model. Coimmunoprecipitation results indicated that aspirin promoted cGAS acetylation in mouse aortic tissue. Western blot and immunohistochemistry results also confirmed that the dimeric amidobenzimidazole compound 3 activated phosphorylation of STING, TBK1, and IRF3 and significantly negatively regulated the expression of GPX4 (glutathione peroxidase). In the β-aminopropionitrile model, dimeric amidobenzimidazole also abolished the protective effect of aspirin.</p><p><strong>Conclusions: </strong>Aspirin confers a protective effect against AAD by promoting cGAS acetylation and inhibiting the cGAS-STING signaling pathway and ferroptosis in VSMC.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324930"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M⁶A Demethylase FTO Targets Pcsk9 to Inhibit Vascular Calcification in Chronic Kidney Disease.","authors":"Yuchen Xie, Huan Zhao, Lan Lan, Rumin Liu, Minhui Zheng, Guoli Zhong, Liang Yuan, Kun Li, Vicky E Macrae, Shengping He, Yao Hao, Liangxi Yuan, Guojun Chen, Dongxing Zhu, Hongjiao Yu","doi":"10.1161/ATVBAHA.126.324532","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.324532","url":null,"abstract":"<p><strong>Background: </strong>FTO (fat mass and obesity-associated) protein, a key N6-methyladenosine demethylase, plays a critical role in cardiovascular disease. However, its function in vascular calcification remains poorly understood.</p><p><strong>Methods: </strong>High phosphate (Pi) was used to induce calcification in vascular smooth muscle cells (VSMCs) and aortic rings, and high-dose vitamin D₃ (vD₃) was used to induce vascular calcification in mice. FTO expression was modulated using adenovirus, adeno-associated virus, and siRNA. To identify FTO targets, we performed integrated MeRIP sequencing and RNA sequencing analyses.</p><p><strong>Results: </strong>FTO expression was significantly downregulated in calcified VSMCs, mouse arteries, and human arteries relative to their noncalcified counterparts. Silencing of <i>Fto</i> increased high Pi-induced osteogenic gene expression and calcification in VSMCs. Conversely, overexpression of <i>Fto</i> resulted in the opposite effect. These results were confirmed in high Pi-induced rat aortic ring calcification and a vD₃-induced mouse model of vascular calcification through treatment with the FTO inhibitor F,B-2,3. Intriguingly, the ALP (alkaline phosphatase) inhibitor TNAP-IN-1 or levamisole hydrochloride partially reduced FTO inhibition-induced increases in VSMC calcification, rat aortic ring calcification, and vascular calcification in mice. Adeno-associated virus-mediated VSMC-specific overexpression of <i>Fto</i> significantly attenuated vascular calcification in mice with overloaded vD₃. Integrated MeRIP sequencing and RNA sequencing identified that <i>Pcsk9</i> is a potential target of FTO. Knockdown of FTO increased N6-methyladenosine methylation and mRNA stability of <i>Pcsk9</i>, and its secretion by VSMCs. In addition, knockdown of <i>Fto</i> enhanced the activation of NF-κB (nuclear factor-κB) signaling and increased the expression of inflammatory cytokines, including <i>IL-6</i>, <i>Icam1</i>, and <i>Vcam1</i>, which were attenuated by concomitant knockdown of <i>Pcsk9</i>. Finally, knockdown of <i>Pcsk9</i> or <i>p65</i> abolished silencing of the <i>Fto</i>-induced increase in osteogenic transition and calcification in VSMCs.</p><p><strong>Conclusions: </strong>Our results suggest that FTO may inhibit vascular calcification at least in part through <i>Pcsk9</i>-mediated modulation of NF-κB signaling and altered ALP activity. FTO may therefore be an attractive target for the treatment of vascular calcification.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms Governing Vascular Function in Heart Failure.","authors":"Valeria Garrido-Moreno, Anwarul Ferdous, Thomas G Gillette, Joseph A Hill","doi":"10.1161/ATVBAHA.126.323132","DOIUrl":"10.1161/ATVBAHA.126.323132","url":null,"abstract":"<p><p>Heart failure is a leading cause of morbidity and mortality worldwide. Emerging evidence points to vascular dysfunction as a major contributor to the development and progression of this grievous syndrome. Functional interplay between the myocardium and vasculature involves endothelial cells, vascular smooth muscle cells, and pericytes governing tissue perfusion, vascular tone, inflammation, and metabolism. Vascular cells play a central role in maintaining cardiovascular homeostasis by sensing hemodynamic and inflammatory stimuli and releasing vasoactive and paracrine factors. Dysregulation of endothelium-derived mediators such as NO, endothelin-1, and endothelium-derived hyperpolarizing factors, along with vascular oxidative stress, inflammation, and vascular remodeling (eg, disturbances in angiogenesis and microvascular rarefaction) impair myocardial perfusion and can accelerate heart failure progression. Here, we summarize key molecular mechanisms linking vascular dysfunction to heart failure, emphasizing endothelial signaling, oxidative stress, inflammation, and angiogenic remodeling.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323132"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13496004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}