Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Procoagulant Effect of Neutrophil Extracellular Traps, Activated Platelets, and Endothelial Cells in Patients After TAVR.","authors":"Wei Wu, Dongxia Tong, Wei Xia, Bin Song, Guangwen Li, Lihui Zhou, Fangyu Xie, Chunquan Zhang, Yvhao Liu, Haiyang Wang, Zhaona Du, Yibing Shao, Jihe Li","doi":"10.1161/ATVBAHA.124.322376","DOIUrl":"10.1161/ATVBAHA.124.322376","url":null,"abstract":"<p><strong>Background: </strong>Patients with severe aortic stenosis, undergoing transcatheter aortic valve replacement (TAVR), are more likely to develop thrombotic complications. However, the definite mechanisms underlying the hypercoagulation state remain unclear to date. Our objectives were to explore whether and how neutrophil extracellular traps (NETs) play a procoagulant role in patients after TAVR alone or TAVR with percutaneous coronary intervention within 1 year and further to evaluate their interactions with platelets and endothelial cells.</p><p><strong>Methods: </strong>The levels of plasma NETs, platelets, and endothelial cell activation markers were analyzed by ELISA. NET formation was observed by immunofluorescence. Procoagulant activity was measured by clotting time, fibrin, and TAT (thrombin-antithrombin) complex generation assays. Phosphatidylserine exposure on cells was assessed by flow cytometry.</p><p><strong>Results: </strong>Compared with pre-TAVR, controls, or severe aortic stenosis without TAVR patients, the plasma NET levels in patients after TAVR alone, especially TAVR with percutaneous coronary intervention, increased from 7 days, peaking at 3 months, and then gradually decreased until the 12th month. Furthermore, neutrophils and plasma from patients post-TAVR are more prone to promote NET formation; NETs from these patients markedly decreased clotting time and increased fibrin and TAT generation. Additionally, a high concentration of NETs induced platelet aggregation and exerted a strong cytotoxic effect on endothelial cells and transformed them into a procoagulant phenotype.</p><p><strong>Conclusions: </strong>These results lead us to believe that NETs contribute to the hypercoagulability in patients post-TAVR. Our study may provide a new target for preventing thrombotic complications in patients post-TAVR by blocking NET generation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1006-1019"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771239","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":"Endothelial Stiffening Induced by CD36-Mediated Lipid Uptake Leads to Endothelial Barrier Disruption and Contributes to Atherosclerotic Lesions.","authors":"Victor Aguilar, Elizabeth Le Master, Amit Paul, Sang Joon Ahn, Dana Lazarko, Maria Febbraio, Dolly Mehta, James C Lee, Irena Levitan","doi":"10.1161/ATVBAHA.124.322244","DOIUrl":"10.1161/ATVBAHA.124.322244","url":null,"abstract":"<p><strong>Background: </strong>Endothelial stiffening induced by Western diet was proposed to be an important factor in vascular dysfunction. In this study, we determine the role of endothelial CD36 (cluster of differentiation 36) in stiffening, disruption of aortic endothelial barrier, and atherosclerosis in mouse models of obesity and hypercholesterolemia.</p><p><strong>Methods: </strong>To address this goal, we generated an endothelial-specific inducible knockdown mouse model of CD36, Cdh5.CreER^T2CD36^fl/fl, on C57/BL6J wild-type and LDLR^-/- genetic backgrounds. Endothelial stiffness is assessed by atomic force microscopy; endothelial barrier integrity is assessed by imaging VE (vascular endothelium)-cadherin junctions and by penetration of Evans blue dye into the aortic wall. Atherosclerotic plaques are quantified using oil red O staining.</p><p><strong>Results: </strong>Endothelial-specific downregulation of CD36 abrogates stiffening of aortic endothelium induced by Western diet in Cdh5.CreER^T2CD36^fl/fl and in Cdh5.CreER^T2CD36^fl/flLDLR^-/- mice. Prevention of Western diet-induced endothelial stiffening by downregulation of CD36 is associated with a protective effect against endothelial barrier disruption in both mouse models and with a significant decrease in the areas of atherosclerotic lesions in Cdh5.CreER^T2CD36^fl/flLDLR^-/- mice. Mechanistically, stiffening of human aortic endothelial cells in vitro is induced by saturated fatty acids, particularly palmitic acid (PA), which results in activation of RhoA. Both PA-induced endothelial stiffening and RhoA activation are abrogated by CD36 siRNA. Furthermore, PA-induced endothelial stiffening of excised aortas ex vivo is lost in aortas isolated from mice, where endothelial CD36 is downregulated. We also demonstrate that PA-induced activation of RhoA and endothelial stiffening require expressing an RhoA-inhibitory protein, Rho-GDI1 (Rho guanosine dissociation inhibitor 1). Finally, we discover that PA disrupts the colocalization of RhoA with Rho-GDI1.</p><p><strong>Conclusions: </strong>We conclude that stiffening of the aortic endothelium by CD36-mediated uptake of fatty acids contributes significantly to Western diet-induced vascular dysfunction and atherosclerosis. We further propose that fatty acids may activate RhoA by inducing its dissociation from Rho-GDI1.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e201-e216"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963825","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":"ALKBH5 Regulates Macrophage Senescence and Accelerates Atherosclerosis by Promoting CCL5 m⁶A Modification.","authors":"Rifeng Gao, Jiaran Shi, Yang Lyu, Bichen Ren, Wei Wei, Jiahui Cheng, Juntao Chen, Yan Zhou, Jianxin Chen, Xiaolei Sun, Jun Jiang, Bo Li, Kun Yang","doi":"10.1161/ATVBAHA.125.322508","DOIUrl":"10.1161/ATVBAHA.125.322508","url":null,"abstract":"<p><strong>Background: </strong>Senescent foamy macrophages are key drivers of atherosclerosis and plaque instability. N⁶-methyladenosine (m⁶A) modification of RNA plays an important role in the development of various diseases including aging. Here, we aim to investigate the role of m⁶A modification of RNA in the formation of senescent foamy macrophages in atherosclerosis.</p><p><strong>Methods: </strong>To assess m⁶A methylation, macrophages were isolated from the atherosclerotic plaques of patients with atherosclerosis, and <i>Apoe^-/-</i> mice were fed a high-fat diet using flow cytometry. An <i>ALKBH5</i> (alkB homolog 5)<i>^f/f</i>, <i>Lyz2</i> (lysozyme 2)<i>^Cre</i>, <i>Apoe^-/-</i> mouse model was generated to determine the infiltration of senescent foamy macrophages into plaques and atherosclerosis progression. Methylated RNA immunoprecipitation, RNA immunoprecipitation sequencing, and dual-luciferase assays were performed to explore the mechanisms underlying the ALKBH5-mediated formation of senescent foamy macrophages.</p><p><strong>Results: </strong>Decreased m⁶A methylation and increased ALKBH5 expression were observed in arterial plaques and infiltrating macrophages from patients and mice with atherosclerosis. Compared with control mice, <i>ALKBH5^f/f</i>, <i>Lyz2^Cre</i>, <i>Apoe^-/-</i> mice exhibited fewer atherosclerosis plaques with greater stability, which was attributed to the suppression of senescent foamy macrophage formation and senescence-associated secretory phenotype. In addition, ALKBH5 deletion reduced the mRNA expression level of CCL5 (CC chemokine ligand 5) by increasing m⁶A methylation in macrophages, which disrupts the stability of <i>CCL5</i> mRNA. Mechanistically, ALKBH5 promoted senescent foamy macrophage formation through the CCL5/CCR5 (CC chemokine receptor 5)/autophagy signaling pathway. CCL5 also recruited CD8⁺ IFN (interferon)γ⁺ T cells via the CCL5-CCR5 axis. The ALKBH5 inhibitor IOX1 (inhibitor of 2OG oxygenases) and the CCR5 antagonist maraviroc were identified as potential clinical interventions for inhibiting senescent foamy macrophage formation and atherosclerosis progression.</p><p><strong>Conclusions: </strong>Myeloid ALKBH5 deletion attenuates atherosclerosis progression by suppressing the formation of senescent foamy macrophages and the recruitment of CD8⁺IFNγ⁺ T cells. These findings identify ALKBH5, CCL5, and CCR5 as novel therapeutic targets for atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"928-944"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771266","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":"Prostaglandins and the Cardiovascular System.","authors":"Emanuela Ricciotti, Garret A FitzGerald","doi":"10.1161/ATVBAHA.124.320744","DOIUrl":"10.1161/ATVBAHA.124.320744","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 6","pages":"841-844"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118688","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":"Regulation of Platelet Function by HDL.","authors":"Marion Pilard, Sara Babran, Catherine Martel","doi":"10.1161/ATVBAHA.124.318260","DOIUrl":"10.1161/ATVBAHA.124.318260","url":null,"abstract":"<p><p>Over the past decade, increasing the capacity of HDL (high-density lipoprotein) cholesterol to mediate macrophage reverse cholesterol transport has been a target of interest in the treatment of cardiovascular diseases (CVDs). However, clinical studies reporting the limited efficacy of HDL or its main apolipoprotein, <i>APOA1</i>, in reducing cardiovascular events have emerged. Although HDL cholesterol is unlikely to play a direct causal role in CVD, its inverse, albeit modest, association with CVD risk, consistently observed in large population studies, suggests it may influence alternative pathways beyond cholesterol metabolism. Given the diverse functions of HDL and its components, it is conceivable that its impact on CVD occurs through less direct mechanisms. A potential hypothesis is that HDL modulates platelet function, a crucial player in the initiation and progression of atherothrombosis, which may contribute to its observed relationship with CVD risk. In this review, we focus on how HDL and its components, with an emphasis on APOA1, interact with platelets (and their precursors or activation products) to modulate atherothrombotic responses.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e184-e200"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968049","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":"NOTCH Signaling Networks in Perivascular Adipose Tissue.","authors":"Christian Potts, Chenhao Yang, Lucy Liaw","doi":"10.1161/ATVBAHA.124.321690","DOIUrl":"10.1161/ATVBAHA.124.321690","url":null,"abstract":"<p><p>Over a hundred years ago, mutants were detected in <i>Drosophila melanogaster</i> that led to a NOTCH in the wing tip. This original phenotype was reflected in the nomenclature of the gene family that was later cloned and characterized in the 1980s and found to be conserved across metazoans. NOTCH signaling relies on transmembrane ligands and receptors that require cellular contact for receptor activation, reflecting its role in multicellular organisms as an intercellular signaling strategy. In humans, mutations in genes encoding <i>NOTCH</i> and their ligands have been shown to promote human disease; these aspects have been extensively reviewed. Notch signaling plays important roles in vascular development (vasculogenesis and angiogenesis) and homeostasis. NOTCH signaling is also active in adipose tissue and contributes to adipocyte differentiation. In addition, NOTCH activity regulates functions of other metabolic organs. This review focuses on NOTCH activity in perivascular adipose tissue within the vascular microenvironment as defined by mouse studies and summarizes expression and potential signaling of the NOTCH signaling network in human perivascular adipose tissue. Due to the strong activity of NOTCH in regulation of metabolic function, activation of the NOTCH network in specific cell types in perivascular adipose tissue has implications for signaling to the underlying blood vessel and control of vascular health and disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"845-856"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953389","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":"Inhibition of LXR Signaling in Human Foam Cells Impairs Macrophage-to-Endothelial Cell Cross Talk and Promotes Endothelial Cell Inflammation.","authors":"Damien Leleu, Thomas Pilot, Léa Mangin, Kevin Van Dongen, Lil Proukhnitzky, Damien Denimal, Maxime Samson, Aline Laubriet, Eric Steinmetz, Mickael Rialland, Léa Pierre, Emma Groetz, Jean-Paul Pais de Barros, Thomas Gautier, Charles Thomas, David Masson","doi":"10.1161/ATVBAHA.125.322448","DOIUrl":"10.1161/ATVBAHA.125.322448","url":null,"abstract":"<p><strong>Background: </strong>During atherogenesis, macrophages turn into foam cells by engulfing lipids present within the atheroma plaques. The shift of foam cells toward proinflammatory or anti-inflammatory phenotypes, a critical step in disease progression, is still poorly understood. LXRs (liver X receptors) play a pivotal role in the macrophage response to lipid, promoting the expression of key genes of cholesterol efflux, mitigating intracellular cholesterol accumulation. LXRs also exert balanced actions on inflammation in human macrophages, displaying both proinflammatory and anti-inflammatory effects.</p><p><strong>Methods: </strong>Our study explored the role of LXRs in the functional response of human macrophage to lipid-rich plaque environment. We used primary human macrophages treated with atheroma plaque extracts and assessed the impact of pharmacological LXR inhibition by GSK2033 on cholesterol homeostasis and inflammatory response. Ultimately, we evaluated macrophage and endothelial cell cross talk by assessing the impact of macrophage-conditioned supernatants on the human endothelial cell.</p><p><strong>Results: </strong>LXR inhibition by GSK2033 resulted in increased levels of cholesterol and oxysterols in human macrophages, alongside notable changes in the cholesterol ester profile. This was accompanied by heightened secretion of proinflammatory cytokines such as IL (interleukin)-6 and TNFα (tumor necrosis factor-α), despite a transcriptional repression of IL-1β. Conditioned media from GSK2033-treated macrophages more effectively activated ICAM-1 (intercellular adhesion molecule-1) and CCL2 (C-C motif ligand 2) expression in endothelial cells.</p><p><strong>Conclusions: </strong>Our findings illustrate the intricate relationship between LXR function, cholesterol metabolism, and inflammation in human macrophages. While LXR is required for the proper handling of plaque lipids by macrophages, the differential regulation of IL-1β versus IL-6/TNFα secretion by LXRs could be challenging for potential pharmacological interventions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"910-927"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953602","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":"Fluid Shear Stress-Regulated Vascular Remodeling: Past, Present, and Future.","authors":"Hanqiang Deng, Anne Eichmann, Martin A Schwartz","doi":"10.1161/ATVBAHA.125.322557","DOIUrl":"10.1161/ATVBAHA.125.322557","url":null,"abstract":"<p><p>The vascular system remodels throughout life to ensure adequate perfusion of tissues as they grow, regress, or change metabolic activity. Angiogenesis, the sprouting of new blood vessels to expand the capillary network, versus regression, in which endothelial cells die or migrate away to remove unneeded capillaries, controls capillary density. In addition, upstream arteries adjust their diameters to optimize blood flow to downstream vascular beds, which is controlled primarily by vascular endothelial cells sensing fluid shear stress (FSS) from blood flow. Changes in capillary density and small artery tone lead to changes in the resistance of the vascular bed, which leads to changes in flow through the arteries that feed these small vessels. The resultant decreases or increases in FSS through these vessels then stimulate their inward or outward remodeling, respectively. This review summarizes our knowledge of endothelial FSS-dependent vascular remodeling, offering insights into potential therapeutic interventions. We first provide a historical overview, then discuss the concept of set point and mechanisms of low-FSS-mediated and high-FSS-mediated inward and outward remodeling. We then cover in vivo animal models, molecular mechanisms, and clinical implications. Understanding the mechanisms underlying physiological endothelial FSS-mediated vascular remodeling and their failure due to mutations or chronic inflammatory and metabolic stresses may lead to new therapeutic strategies to prevent or treat vascular diseases.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"882-900"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957265","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":"Correction to: Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets.","authors":"Hannah J Larsen, Daire Byrne, Tahsin Özpolat, Aastha Chauhan, S Lawrence Bailey, Nicole Rhoads, Franklin Reed, Massiel C Stolla, Reheman Adili, Michael Holinstat, Xiaoyun Fu, Moritz Stolla","doi":"10.1161/ATV.0000000000000185","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000185","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 6","pages":"e231"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118687","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":"Using Genomics to Develop Personalized Cardiovascular Treatments.","authors":"Mihir M Sanghvi, William J Young, Hafiz Naderi, Richard Burns, Julia Ramírez, Christopher G Bell, Patricia B Munroe","doi":"10.1161/ATVBAHA.125.319221","DOIUrl":"10.1161/ATVBAHA.125.319221","url":null,"abstract":"<p><p>Advances in genomic technologies have significantly enhanced our understanding of both monogenic and polygenic etiologies of cardiovascular disease. In this review, we explore how the utilization of genomic information is bringing personalized medicine approaches to the forefront of cardiovascular disease management. We describe how genomic data can resolve diagnostic uncertainty, support cascade screening, and inform treatment strategies. We discuss how genome-wide association studies have identified thousands of genetic variants associated with polygenic cardiovascular diseases, and how integrating these insights into polygenic risk scores can enhance personalized risk prediction beyond traditional clinical algorithms. We detail how pharmacogenomics approaches leverage genotype information to guide drug selection and mitigate adverse events. Finally, we present the paradigm-shifting approach of gene therapy, which holds the promise of being a curative intervention for cardiovascular conditions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"866-881"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953390","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}