Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Endothelium- and Fibroblast-Derived C-Type Natriuretic Peptide Prevents the Development and Progression of Aortic Aneurysm.","authors":"Aisah A Aubdool, Amie J Moyes, Cristina Perez-Ternero, Reshma S Baliga, Jaspinder Singh Sanghera, M Taaha Syed, Kareemah Jaigirdar, Anmolpreet K Panesar, Janice C Tsui, Yanming Li, Hernan G Vasquez, Ying H Shen, Scott A LeMaire, Juliette Raffort, Ziad Mallat, Hong S Lu, Alan Daugherty, Adrian J Hobbs","doi":"10.1161/ATVBAHA.124.322350","DOIUrl":"10.1161/ATVBAHA.124.322350","url":null,"abstract":"<p><strong>Background: </strong>Thoracic (TAA) and abdominal (AAA) aortic aneurysm are life-threatening diseases characterized by dilation, inflammation, and structural weakness; development of pharmacological therapies is desperately needed. CNP (C-type natriuretic peptide) plays a key role in vascular homeostasis, mediating vasodilator, anti-inflammatory, and antiatherogenic actions. Since such processes drive AA, we determined the role of endogenous CNP in offsetting pathogenesis.</p><p><strong>Methods: </strong>Tissue from patients with AA was analyzed to determine the consequences on CNP signaling. Ascending and suprarenal aortic diameters were assessed at baseline and following Ang II (angiotensin II; 1.44 mg/kg per day) infusion in wild-type, endothelium-restricted (ecCNP^-/-), fibroblast-restricted (fbCNP^-/-), global CNP (gbCNP^-/-), or global NPR-C^-/- mice infected with an adeno-associated virus expressing a proprotein convertase subtilisin/kexin type 9 gain-of-function mutation or backcrossed to an apoE^-/- background. At 28 days, aortas were harvested for RT-qPCR (quantitative reverse transcription polymerase chain reaction) and histological analyses. CNP (0.2 mg/kg per day) was infused to rescue any adverse phenotype.</p><p><strong>Results: </strong>Aneurysmal tissue from patients with TAA and AAA revealed that CNP and NPR-C (natriuretic peptide receptor-C) expression were overtly perturbed. ecCNP^-/-, fbCNP^-/-, and gbCNP^-/- mice exhibited an aggravated phenotype compared to wild-type animals in both ascending and suprarenal aortas, exemplified by greater dilation, fibrosis, elastin degradation, and macrophage infiltration. CNP and NPR-C expression was also dysregulated in murine thoracic AA and abdominal AA, accompanied by increased accumulation of mRNA encoding markers of inflammation, extracellular matrix remodeling/calcification, fibrosis, and apoptosis. CNP also prevented activation of isolated macrophages and vascular smooth muscle cells. An essentially identical phenotype was observed in NPR-C^-/- mice and while administration of CNP protected against disease severity in wild-type animals, this phenotypic rescue was not apparent in NPR-C^-/- mice.</p><p><strong>Conclusions: </strong>Endothelium- and fibroblast-derived CNP, via NPR-C activation, plays important roles in attenuating AA formation by preserving aortic structure and function. Therapeutic strategies aimed at mimicking CNP bioactivity hold potential to reduce the need for surgical intervention.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1044-1063"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771220","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":"Platelet-Derived PDGF-A Disrupts Blood-Brain Barrier Integrity in Ischemic Stroke-Brief Report.","authors":"Vanessa Göb, Lena Zimmermann, Katherina Hemmen, Axel Haarmann, Katrin G Heinze, Michael K Schuhmann, David Stegner","doi":"10.1161/ATVBAHA.125.321191","DOIUrl":"10.1161/ATVBAHA.125.321191","url":null,"abstract":"<p><strong>Background: </strong>Ischemic stroke (IS) is a prevalent cause of death and disability worldwide. Cerebral ischemia induces profound changes at the blood-brain barrier, which lead to a remarkable increase in paracellular permeability, worsening outcomes. Platelets are well known for safeguarding vascular integrity and the prevention of bleeding complications. On the other hand, platelet activation contributes to infarct progression in the context of IS. The manifold, context-dependent roles of platelets, however, have not yet been resolved.</p><p><strong>Methods: </strong>IS was mimicked by transient middle cerebral artery occlusion in wild-type, transgenic, or treated mice, and vascular leakage was assessed by intravital 2-photon microscopy, as well as Western blotting and immunohistochemistry. Barrier property of primary murine brain microvascular endothelial cells was measured as transendothelial electrical resistance of cellular monolayers in response to platelet releasate or recombinant proteins.</p><p><strong>Results: </strong>IS induces blood-brain barrier breakdown characterized by time-dependent leakage of albumin in the brain parenchyma. We could show that local platelet activation triggers the release of PDGF (platelet-derived growth factor)-A from α-granules, which induces the loss of brain endothelial cell layer integrity. This translates to a comprised vascular integrity in vivo. In the absence of α-granule content (<i>Nbeal2</i>^<i>-/-</i>) or pharmacological blockade of PDGF, no disruption of the endothelial layer or vascular leakage was observed.</p><p><strong>Conclusions: </strong>PDGF-A released from platelets impairs blood-brain barrier integrity, resulting in detrimental vascular leakage and infarct progression. These findings provide important insights on the pivotal role of platelets in IS further elucidating the mechanisms of thrombo-inflammation in the brain.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1166-1174"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075597","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":"Afadin Promotes Vascular Smooth Muscle Cell Contraction by Interacting With Phospholipase C to Enhance Ca²⁺ Signaling for Blood Pressure Regulation.","authors":"Md Mahbubur Rahman Khan, Akira Sato, Akio Shimizu, Shunji Suetaka, Md Rasel Molla, Masahiro Komeno, Mst Zenika Nasrin, Masanari Nishida, Futoshi Toyoda, Munehito Arai, Hisakazu Ogita","doi":"10.1161/ATVBAHA.125.322619","DOIUrl":"10.1161/ATVBAHA.125.322619","url":null,"abstract":"<p><strong>Background: </strong>Vascular smooth muscle cells (VSMCs) regulate vascular tone and blood pressure. Stimulation of VSMCs with vasoconstrictors, such as AngII (angiotensin II) or norepinephrine, activates the G-protein-coupled receptor-mediated cascade, leading to a hypercontractile state and vascular remodeling. Afadin, an intracellular adaptor protein that mainly localizes at cell-cell junctions, regulates various biological phenomena. However, its role in VSMCs remains unclear.</p><p><strong>Methods: </strong>VSMCs were isolated from newly generated VSMC-specific afadin conditional knockout mice. A small peptide (7 amino acids) designed in silico to inhibit the afadin-PLC (phospholipase C) β association was administered to the mouse VSMCs and aortic media using adeno-associated virus.</p><p><strong>Results: </strong>Unlike control mice, afadin conditional knockout mice did not exhibit AngII- or norepinephrine-induced elevation in blood pressure. VSMCs isolated from afadin conditional knockout mice were less responsive to AngII- or norepinephrine-induced cell contractility compared with control VSMCs, as evidenced by reduced release of intracellular Ca²⁺ resulting from lowered production of AngII- or norepinephrine-induced inositol 1,4,5-trisphosphate. Mechanistically, the PDZ (disk large tumor suppressor, zonula occludens-1) domain of afadin was shown to associate with the C terminus of PLCβ, providing support for the localization of PLCβ on the plasma membrane, where it generates inositol 1,4,5-trisphosphate. Furthermore, the newly designed small peptide, which inhibited the afadin-PLCβ association, attenuated AngII-induced cell contractility and intracellular Ca²⁺ release in vitro and blocked AngII-stimulated blood pressure elevation in vivo.</p><p><strong>Conclusions: </strong>Afadin expression in VSMCs promotes cell contraction by interacting with PLCβ to enhance Ca²⁺ signaling and has potential as a novel molecular target for blood pressure regulation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1226-1243"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172547","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":"Nitrosation of CD36 Regulates Endothelial Function and Serum Lipids.","authors":"Melissa A Luse, Wyatt J Schug, Luke S Dunaway, Shruthi Nyshadham, Skylar A Loeb, Alicia Carvalho, Rachel Tessema, Caitlin Pavelec, T C Stevenson Keller, Xiaohong Shu, Claire A Ruddiman, Anna Kosmach, Timothy M Sveeggen, Ray Mitchell, Pooneh Bagher, Richard D Minshall, Norbert Leitnger, Linda Columbus, Kandice R Levental, Ilya Levental, Miriam Cortese-Krott, Brant E Isakson","doi":"10.1161/ATVBAHA.124.321964","DOIUrl":"10.1161/ATVBAHA.124.321964","url":null,"abstract":"<p><strong>Background: </strong>During obesity, endothelial cells (ECs) become lipid laden, leading to endothelial dysfunction. We tested posttranslational modification on cluster of differentiation 36 (CD36) that may regulate EC lipid accumulation.</p><p><strong>Methods: </strong>We used an EC-specific Cav1 (caveolin-1) knockout mouse, nitrosation and palmitoylation assays, and whole animal Nγ-nitro-l-arginine methyl ester administration to examine blood lipids.</p><p><strong>Results: </strong>EC-specific Cav1 knockout male mice are hyperlipidemic regardless of diet but retain endothelial cell function. We found these mice have significantly increased NO in response to the lack of Cav1, and the presence or absence of NO toggled inversely EC lipid content and plasma lipid in mice. The NO nitrosated the fatty acid translocase CD36 at the same cysteines that are palmitoylated on CD36. The nitrosation of CD36 prevented its trafficking to the plasma membrane and decreased lipid accumulation. The physiological effect of this mechanism was a reliance on NO for endothelial function and not dilation.</p><p><strong>Conclusions: </strong>This work suggests that CD36 nitrosation occurs as a protective mechanism to prevent EC lipotoxicity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1067-1086"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966202","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":"Multiomic Landscape of Extracellular Vesicles in Human Carotid Atherosclerotic Plaque Reveals Endothelial Communication Networks.","authors":"Sneha Raju, Mandy E Turner, Christian Cao, Majed Abdul-Samad, Neil Punwasi, Mark C Blaser, Rachel M E Cahalane, Steven R Botts, Kamalben Prajapati, Sarvatit Patel, Ruilin Wu, Dakota Gustafson, Natalie J Galant, Lindsey Fiddes, Melody Chemaly, Ulf Hedin, Ljubica Matic, Michael A Seidman, Vallijah Subasri, Sasha A Singh, Elena Aikawa, Jason E Fish, Kathryn L Howe","doi":"10.1161/ATVBAHA.124.322324","DOIUrl":"10.1161/ATVBAHA.124.322324","url":null,"abstract":"<p><strong>Background: </strong>Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque.</p><p><strong>Methods: </strong>EVs were enriched via size exclusion chromatography from human carotid endarterectomy samples dissected into paired plaque and marginal zones (symptomatic n=16, asymptomatic n=13). EV-cargos were assessed via whole transcriptome microRNA-sequencing and mass spectrometry-based proteomics. EV multiomics was integrated with bulk and single-cell RNA-sequencing datasets to predict EV cellular origin and ligand-receptor interactions, and multimodal biological network integration of EV-cargo was completed. EV functional impact was assessed with endothelial angiogenesis assays.</p><p><strong>Results: </strong>Carotid plaques contained more EVs than adjacent marginal zones, with differential enrichment for EV-microRNAs and EV-proteins in key atherogenic pathways. EV cellular origin analysis suggested that tissue EV signatures originated from endothelial cells, smooth muscle cells, and immune cells. Integrated tissue vesiculomics and single-cell RNA-sequencing indicated complex EV-vascular cell communication that changed with disease progression and plaque vulnerability (ie, symptomatic disease). Plaques from symptomatic patients, but not asymptomatic patients, were characterized by increased involvement of endothelial pathways and more complex ligand-receptor interactions, relative to their marginal zones. Plaque EVs were predicted to mediate communication with endothelial cells. Pathway enrichment analysis delineated an endothelial signature with roles in angiogenesis and neovascularization, well-known indices of plaque instability. This was validated functionally, wherein human carotid symptomatic plaque EVs induced sprouting angiogenesis in comparison to their matched marginal zones.</p><p><strong>Conclusions: </strong>Our findings indicate that EVs may drive dynamic changes in plaques through EV-vascular cell communication and effector functions that typify vulnerability to rupture, precipitating symptomatic disease. The discovery of endothelial-directed angiogenic processes mediated by EVs creates new therapeutic avenues for atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1277-1305"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172552","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: C-X-C Ligand 16 Is an Independent Predictor of Cardiovascular Death and Morbidity in Acute Coronary Syndromes.","authors":"Thomas Andersen, Thor Ueland, Tatevik Ghukasyan Lakic, Axel Åkerblom, Maria Bertilsson, Pål Aukrust, Annika E Michelsen, Stefan K James, Richard C Becker, Robert F Storey, Lars Wallentin, Agneta Siegbahn, Frederic Kontny","doi":"10.1161/ATV.0000000000000187","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000187","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 7","pages":"e336"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493822","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":"C-Type Natriuretic Peptide: Protecting the Aorta.","authors":"S Jeson Sangaralingham, John C Burnett","doi":"10.1161/ATVBAHA.125.322802","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322802","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 7","pages":"1064-1066"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493823","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":"Elevated Plasma MBL Levels Are Associated With Risk of Future Venous Thromboembolism: The HUNT Study.","authors":"Christabel Esi Damoah, Solveig M Valderhaug, Omri Snir, Kristian Dalsbø Hindberg, Sigrid K Brækkan, Steven P Grover, Therese H Nøst, Péter Gál, Gábor Pál, Christian Jonasson, Peter Garred, Tom Eirik Mollnes, Kristian Hveem, John-Bjarne Hansen","doi":"10.1161/ATVBAHA.124.322052","DOIUrl":"10.1161/ATVBAHA.124.322052","url":null,"abstract":"<p><strong>Background: </strong>MBL (mannose-binding lectin), a pattern recognition molecule circulating in complex with MASPs (MBL-associated serine proteases), activates the lectin complement pathway and facilitates thrombin generation upon binding to specific moieties on pathogens or altered host cells. We aimed to investigate the association between plasma MBL levels and risk of future venous thromboembolism (VTE) and to explore the effect of MBL-MASP-1/2 complexes on thrombin generation.</p><p><strong>Methods: </strong>We conducted a population-based case-cohort (294 VTE patients, 1066 sex- and age-weighted subcohorts) derived from HUNT (The Trøndelag Health Study). Plasma MBL levels were measured using the SomaScan 7k aptamer-based platform. Cox proportional hazards regression models were used to estimate hazard ratios for VTE across quartiles of MBL levels. Thrombin generation in plasma induced by MBL-MASPs complexes was assessed in vitro.</p><p><strong>Results: </strong>Subjects with MBL levels in the highest quartile had a 79% higher risk of overall VTE (hazard ratio, 1.79 [95% CI, 1.23-2.61]) than those with MBL levels in the lowest quartile after multivariable adjustments. The risk estimates by high plasma MBL were particularly strong for deep vein thrombosis (hazard ratio, 2.50 [95% CI, 1.42-4.37]) and unprovoked VTE (hazard ratio, 2.81 [95% CI, 1.53-5.16]). MBL-MASP-1/2 complexes promoted complement activation and thrombin generation, and monospecific inhibitors abolished their enzymatic activity.</p><p><strong>Conclusions: </strong>Our findings support the notion that high plasma MBL levels are associated with an increased risk of future VTE and suggest that the risk increase is partially mediated through the initiation of thrombin generation by MBL-MASP-1/2 complexes at the site of venous thrombosis formation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324-e335"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075592","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":"Metabolic Rewiring in Calcific Aortic Valve Disease: It Goes Beyond Immunometabolism.","authors":"Adrien Lupieri","doi":"10.1161/ATVBAHA.125.322959","DOIUrl":"10.1161/ATVBAHA.125.322959","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1041-1043"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172550","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":"Correction to: Activated Platelets Induce Endothelial Cell Inflammatory Response in Psoriasis via COX-1.","authors":"Michael S Garshick, Michael Tawil, Tessa J Barrett, Charissa M Salud-Gnilo, Michael Eppler, Angela Lee, Jose U Scher, Andrea L Neimann, Sanja Jelic, Nehal N Mehta, Edward A Fisher, James G Krueger, Jeffrey S Berger","doi":"10.1161/ATV.0000000000000186","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000186","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 7","pages":"e337"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493821","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}