Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Single-Cell Proteomics Uncovers Cell-Specific Proteins in Vascular Health and Marfan Syndrome Disease-Brief Report.","authors":"Junedh M Amrute, Lihua Jiang, Nikhita Bolar, Kelly Higa, Chenchen Zhu, Ruiqi Jian, Jennifer Kim, Matthew Duda, Anna Marie Puaala, Avani Klinder, Alex Dalal, Albert J Pedroza, Dieter P Reinhardt, Paul Cheng, Michael P Snyder, Michael P Fischbein","doi":"10.1161/ATVBAHA.125.324104","DOIUrl":"10.1161/ATVBAHA.125.324104","url":null,"abstract":"<p><strong>Background: </strong>The vascular system is the largest organ in the body and underlies most chronic diseases, yet the molecular mechanisms that govern its plasticity remain poorly defined.</p><p><strong>Methods: </strong>We applied single-cell proteomics in vascular disease, integrating it with single-cell transcriptomics to map protein regulation in healthy and Marfan syndrome aortas.</p><p><strong>Results: </strong>This approach uncovered cell type-specific and cell state-specific proteins missed at the transcriptional level. Notably, we identified a decoupling of fibrillin-1 RNA and protein abundance, suggesting altered protein regulation as a potential contributor to aortic degeneration. Single-cell proteomics further resolved modulated smooth muscle cell states enriched for matrix effectors (AEBP1 [adipocyte enhancer binding protein 1], HTRA1 [high-temperature requirement A serine peptidase 1], FN1 [fibronectin 1]) and uniquely protein-level regulators (GLIPR2 [GLI pathogenesis-related 2], ITGB2 [integrin beta-2], and CD151 [cluster of differentiation 151 antigen]).</p><p><strong>Conclusions: </strong>Together, these findings establish the human single-cell proteomic atlas of the aorta, reveal altered FBN1 (fibrillin-1) protein regulation in both human and mouse Marfan syndrome, and position single-cell proteomics as a transformative framework for decoding vascular plasticity and identifying actionable effectors in disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324104"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720105","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":"Relaxin-3/RXFP1 Axis Regulates the Phenotypic Switch of Diabetic Vascular Smooth Muscle Cells by Inhibiting H3K18la-Mediated Egfr Transcription.","authors":"Jiaxin Xue, Jingzhi Wang, Yuxin Yang, Xinfang Liang, Xiaoqi Liu, Siting Hong, Xiao Ma, Xiaohui Zhang","doi":"10.1161/ATVBAHA.126.324338","DOIUrl":"10.1161/ATVBAHA.126.324338","url":null,"abstract":"<p><strong>Background: </strong>The phenotypic switching of vascular smooth muscle cells (VSMCs) is a critical pathophysiological mechanism of diabetic vascular remodeling. There is increasing evidence indicating that endogenous relaxin-3 exhibits cardiovascular effects, including vasodilation, reversal of ventricular remodeling, and attenuation of myocardial fibrosis. This study investigates the role of relaxin-3 as a key regulator in the phenotypic switching of VSMCs and elucidates its underlying mechanisms.</p><p><strong>Methods: </strong>We generated a diabetic rat model to investigate the biological roles of relaxin-3 in diabetic vascular remodeling. Metabolomic profiling characterized relaxin-3-induced metabolic changes in VSMCs under high glucose treatment. Combined chromatin immunoprecipitation sequencing and RNA sequencing data were used to further investigate the gene regulatory mechanisms of relaxin-3 in the phenotypic switching of VSMCs and target genes regulated by H3K18la (histone H3 lysine 18 lactylation).</p><p><strong>Results: </strong>Relaxin-3 and its receptor RXFP1 (relaxin family peptide receptor 1) were upregulated in diabetic human and rat aortas. Silencing of relaxin-3 or RXFP1 expression inhibited VSMC contractile phenotype protein expression and promoted VSMC proliferation. Relaxin-3 treatment mitigated the phenotypic switching of VSMCs via RXFP1, preserving VSMCs' contractile phenotype. Further, relaxin-3 treatment lowered the glycolytic rate and lactate production during the phenotypic switching of VSMCs and decreased histone lactylation. Mechanistically, relaxin-3 suppressed LDHA (lactate dehydrogenase A)-mediated lactate production and H3K18la-mediated <i>Egfr</i> (epidermal growth factor receptor) transcription, and blocked PKM2 (pyruvate kinase M2) nuclear translocation, thereby preventing PKM2/β-catenin complex formation.</p><p><strong>Conclusions: </strong>Relaxin-3 alleviated the phenotypic switching of diabetic VSMCs through a dual mechanism: inhibiting lactate-mediated H3K18la and disrupting the intranuclear PKM2/β-catenin interaction, thereby preserving the contractile VSMC phenotype.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324338"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824064","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":"MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.","authors":"Jianjin Wu, Lei Wang, Fukang Zou, Fangbing Liu, Guanyu Fang, Kai Cheng, Haochen Gao, Kangkang Zhi, Lefeng Qu","doi":"10.1161/ATVBAHA.126.324585","DOIUrl":"10.1161/ATVBAHA.126.324585","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is driven by metabolic-immune crosstalk, in which trained immunity sustains vascular inflammation. MAP17 (membrane-associated protein 17), a redox- and metabolism-regulating adaptor protein, functions as a potential upstream driver of SGLT2 (sodium-glucose cotransporter 2). We aimed to determine whether MAP17 links hyperglycemia to glycolytic activation, inflammatory polarization, and plaque progression in atherosclerosis.</p><p><strong>Methods: </strong>MAP17 expression and its correlations with clinical risk factors were analyzed in serum from 30 patients with atherosclerosis. A trained immunity model was established in bone marrow-derived macrophages via sustained high glucose and IFN-γ (interferon-γ)/lipopolysaccharide stimulation. Functional assays were performed after MAP17 overexpression/knockdown, SGLT2 silencing, or glycolysis inhibition.</p><p><strong>Results: </strong>MAP17 was significantly coupregulated in patients with atherosclerosis, with the highest levels observed in those with concomitant diabetes or metabolic syndrome, and closely associated with elevated proinflammatory M1-like cytokines. Immunohistochemistry of carotid plaques confirmed its colocalization with SGLT2 within CD68⁺ macrophage-rich, lipid-laden, and inflamed regions. In bone marrow-derived macrophages, high glucose robustly induced MAP17 expression, which unidirectionally upregulated SGLT2, enhanced glycolytic flux, increased lactate production, and promoted M1-like polarization and foam cell formation. MAP17 knockdown markedly suppressed SGLT2 expression, glycolysis, and TNF-α (tumor necrosis factor-α)/IL (interleukin)-1β secretion, whereas MAP17 overexpression restored glycolytic activity, proinflammatory phenotype, and foam cell generation even in SGLT2-deficient cells. In diabetic chimeric <i>Apoe</i>^<i>-/-</i> mice, MAP17 activation correlated with increased glycolytic marker expression, higher proinflammatory M1-like macrophage ratios, aggravated vascular inflammation, and greater plaque burden; these effects were mitigated by MAP17 or SGLT2 silencing, or by glycolysis inhibition.</p><p><strong>Conclusions: </strong>MAP17 is a key upstream controller of the SGLT2-glycolysis axis that promotes trained immunity and accelerates atherosclerosis. Targeting MAP17 may disrupt the metabolic-inflammatory feedback loop and represents a promising therapeutic strategy for diabetic atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324585"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878845","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":"Targeting cGAS-STING and Ferroptosis in Aortic Disease: Another Aspirin Discovery.","authors":"A Phillip Owens, Tyler W Benson","doi":"10.1161/ATVBAHA.126.325325","DOIUrl":"10.1161/ATVBAHA.126.325325","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325325"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148824051","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":"Extracellular Vesicle Eicosanoids Mediate Monocyte Migration.","authors":"Saikal Shamkeeva, Saira Ambreen, Shihai Jiang, Madlen Reinicke, Zhiyang Li, Rajiv Rana, Ahmed Elwakiel, Caroline Schmidt, Ulf Wagner, Berend Isermann, Uta Ceglarek, Mitja L Heinemann","doi":"10.1161/ATVBAHA.126.324954","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.324954","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs) moderate a variety of physiological and pathological processes by enabling the intercellular transfer of proteins, nucleic acids, and lipids. Bioactive lipids such as polyunsaturated fatty acids or eicosanoids play an important role in propagation and resolution of inflammation and in vascular regulation. We previously found that the lipid composition of macrophage-derived EVs depends on polarization of the originating macrophages.</p><p><strong>Methods: </strong>In this study, we investigated the role of EV-contained 12-LOX (12-lipoxygenase) metabolites in the moderation of inflammation. We used in vitro functional cell culture models as well as an in vivo sterile peritonitis model with male wild-type mice.</p><p><strong>Results: </strong>We found increased levels of these 12-LOX products in M1 macrophages and M1 macrophage-derived EVs. Inhibition of 12-LOX led to significantly lower levels of 12-LOX metabolites in M1 EVs and attenuated M1 EV-mediated proinflammatory effects such as production of MCP-1 (monocyte chemoattractant protein 1) and CXCL10 (C-X-C motif chemokine ligand 10). M1 EVs induced monocyte adhesion and migration, which were also reduced by 12-LOX inhibition. In a sterile peritonitis model, M1 EVs increased the migration of monocytes into the peritoneum and the presence of macrophages in the peritoneal wall. Both effects were diminished by 12-LOX inhibition.</p><p><strong>Conclusions: </strong>Our results show that the specific lipid profile in macrophage-derived EVs is functionally relevant during inflammation. We demonstrate that eicosanoids in M1 macrophage-derived EVs educate other cells towards a proinflammatory phenotype, promoting inflammation and endothelial dysfunction.</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":"149103307","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":"PET Imaging in Pulmonary Hypertension.","authors":"Mandy M T van Leent, Trea St Hillaire, Sanjay Sivalokanathan, Hidetaka Morita, Philip M Robson, Kiyotake Ishikawa, Maria Giovanna Trivieri","doi":"10.1161/ATVBAHA.126.324761","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.324761","url":null,"abstract":"<p><p>Pulmonary hypertension comprises a heterogeneous group of diseases characterized by elevated pulmonary arterial pressures and progressive right ventricular (RV) remodeling, with RV failure as the principal determinant of outcome. This review discusses positron emission tomography (PET) imaging across pulmonary hypertension, with particular emphasis on pulmonary arterial hypertension, in which pulmonary vascular remodeling and RV adaptation are central disease features. Although echocardiography and cardiac magnetic resonance imaging provide robust assessment of RV structure, function, and fibrosis, they are limited in detecting early molecular alterations that precede overt dysfunction. PET offers a unique opportunity to visualize these processes. In particular, [¹⁸F]fluorodeoxyglucose PET has demonstrated a shift in RV substrate utilization from fatty acid oxidation toward glycolysis, reflecting metabolic stress and maladaptation. More recently, fibroblast activation protein inhibitor PET has emerged as a promising modality, with first-in-human studies in pulmonary arterial hypertension demonstrating uptake in the RV and pulmonary vasculature, consistent with active remodeling. Beyond fibroblast activation, additional metabolic and immunologic targets may provide complementary insight into pulmonary vascular disease activity, RV remodeling, and treatment response. Together, these advances position PET as a powerful tool for early detection, phenotyping, and risk stratification in pulmonary hypertension, with particular relevance for pulmonary arterial hypertension.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103346","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":"KLF4 in Smooth Muscle Cell-Derived Progenitor Cells Is Essential for Angiotensin II-Induced Cardiac Inflammation and Fibrosis.","authors":"Sizhao Lu, Tysen Noble, Jake Elkins, Austin J Jolly, Allison M Dubner, Jeffrey G Jacot, Brisa Peña Castellanos, Elizabeth J Hardy, Raphael A Nemenoff, Karen S Moulton, Mark W Majesky, Mary C M Weiser-Evans","doi":"10.1161/ATVBAHA.126.324849","DOIUrl":"10.1161/ATVBAHA.126.324849","url":null,"abstract":"<p><strong>Background: </strong>Cardiac fibrosis is defined by the excessive accumulation of ECM (extracellular matrix) material resulting in cardiac tissue scarring and dysfunction. Although it is commonly accepted that myofibroblasts are the major contributors to ECM deposition in cardiac fibrosis, their origin remains controversial. Our group discovered that a subpopulation of resident vascular stem cells residing within the artery adventitia (termed adventitial Sca1+ smooth muscle-derived progenitor cells [AdvSca1-SM]) originates from mature vascular smooth muscle cells through a KLF4 (Kruppel-like factor 4)-dependent in situ reprogramming process. However, the molecular mechanism(s) whereby KLF4 regulates the AdvSca1-SM phenotype remain unclear.</p><p><strong>Methods: </strong>We leveraged a highly specific AdvSca1-SM cell reporter system, single-cell RNA-sequencing, and spatial transcriptomic approaches to examine the spatiotemporal differentiation trajectory of AdvSca1-SM cells in AngII (angiotensin II) challenged cardiac tissues. To examine the function of KLF4, we compared the cardiac inflammation and fibrotic response of wild-type and AdvSca1-SM-specific <i>Klf4</i> knockout mice.</p><p><strong>Results: </strong>We demonstrate the profibrotic differentiation trajectory of coronary artery-associated AdvSca1-SM cells in cardiac fibrosis, characterized by loss of stemness-related genes, including <i>Klf4</i>, but gain of expression of a profibrotic phenotype. Importantly, these changes were recapitulated in human cardiac hypertrophic tissue, supporting the translational significance of a profibrotic transition of AdvSca1-SM-like cells in human cardiomyopathy. Spatially, AdvSca1-SM cells expand from the adventitia to the cardiac interstitium while exhibiting close association with T cells. AdvSca1-SM cell-specific knockout of <i>Klf4</i> before AngII treatment paradoxically protected against cardiac T-cell inflammation, fibrosis, and systolic dysfunction.</p><p><strong>Conclusions: </strong>Overall, our data reveal the contribution of AdvSca1-SM cells to myofibroblasts in the setting of AngII-induced cardiac fibrosis. KLF4 not only maintains the stemness of AdvSca1-SM cells but also orchestrates their response to profibrotic stimuli and interactions with T cells. KLF4 may serve as a therapeutic target in cardiac fibrosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324849"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13571780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787586","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: FUT8-Dependent Core Fucosylation: Essential for Platelet Function and a Target in Thrombosis.","authors":"Ruey-Bing Yang, Cheng-Fen Tu, Yan-Ting Chen, The Huong Chau, Shu-Wha Lin, Cheng-Da Tsai, Fu-An Li, Morten Thaysen-Andersen, Yuh-Charn Lin","doi":"10.1161/ATV.0000000000000199","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000199","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"46 10","pages":"e000199"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029669","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":"Empagliflozin Improves Angina and Endothelial Dysfunction Indices in Angina and No Obstructive Coronary Arteries (ANOCA).","authors":"Danielle N Tapp, Sukhleen Kaur, Olga Toleva, Paxson Tipler, Namrita Ashokprabhu, Pooja Acharya, Christian W Schmidt, Leslie Korbee, Michelle Hamstra, Michael Tranter, Andreas Tzoumas, Ayushi Mohan, Shesh N Rai, Dirk J Duncker, John Beltrame, Steve Miner, C Noel Bairey Merz, Timothy D Henry, A Phillip Owens, Odayme Quesada","doi":"10.1161/ATVBAHA.126.324735","DOIUrl":"10.1161/ATVBAHA.126.324735","url":null,"abstract":"<p><strong>Background: </strong>Treatments targeting endothelial dysfunction in patients with angina and no obstructive coronary arteries (ANOCA) and coronary microvascular and vasomotor dysfunction (CMVD) are lacking. We evaluated the effects of SGLT2i (sodium-glucose cotransporter-2 inhibition) on angina, inflammatory and oxidative stress biomarkers, and endothelial dysfunction indices using a serum-induced in vitro model in ANOCA patients with CMVD. We conducted an open-label pilot trial of 11 ANOCA participants with CMVD diagnosed by invasive coronary function testing receiving empagliflozin (10 mg daily) for 90 days.</p><p><strong>Methods: </strong>Angina (Seattle Angina Questionnaire), circulating inflammatory and oxidative stress biomarkers, and endothelial microvesicles (eEVs) were assessed from baseline to 45 and 90 days, and from 90 days to posttreatment discontinuation in a subset (N=5). A serum-induced in vitro model of human coronary artery endothelial cells was used to evaluate endothelial cell apoptosis, viability, eEV release, VCAM-1 (vascular cell adhesion molecule-1) expression, and mitochondrial reactive oxygen species. Stored serum from ANOCA patients without CMVD (controls, N=6) was compared with baseline samples.</p><p><strong>Results: </strong>All trial participants had coronary endothelial dysfunction, with concomitant coronary microvascular dysfunction (55%), coronary spasm (54%), and microvascular spasm (18%). Empagliflozin significantly improved Seattle Angina Questionnaire summary scores by 14.0 (4.2-23.9) points at 90 days (<i>P</i><0.001). Compared with baseline, empagliflozin significantly reduced inflammatory cytokines, oxidative stress biomarkers, and inflammatory eEVs while increasing anti-inflammatory cytokines, antioxidants, and repair eEVs at 45 and 90 days; these effects rebounded after treatment discontinuation. Similarly, serum collected during empagliflozin treatment significantly reduced endothelial cell apoptosis, eEV release, VCAM-1 expression, and mitochondrial reactive oxygen species in vitro, with reversal of these effects at posttreatment discontinuation.</p><p><strong>Conclusions: </strong>In ANOCA participants with invasive coronary function testing confirmed CMVD, SGLT2i therapy produced clinically meaningful anti-anginal effects and reversed multiple indices of endothelial dysfunction, with rebound after treatment discontinuation. These findings support further evaluation in larger clinical trials.</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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103277","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":"Gas-6 Scavenges Anionic Phospholipid-Expressing Microparticles and Mitigates TBI-Induced Endotheliopathy and Coagulopathy in Mice.","authors":"Hao Zhang, Yuyang Miao, Tianrui Ma, Xiaoyang Zhang, Yuhua Wang, Yichi Zhang, Min Wang, Kaifeng Pang, Zijian Zhou, Pengbo Zhao, Lujia Tang, Chenyang Liu, Xiangru Ren, Yafan Liu, Yang Li, Guili Yang, Min Li, Jing-Fei Dong, Zilong Zhao","doi":"10.1161/ATVBAHA.126.324955","DOIUrl":"10.1161/ATVBAHA.126.324955","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) results in the release of microparticles from injured brain cells into circulation. These microparticles induce a systemic hypercoagulable state that rapidly transitions into secondary coagulopathy and endotheliopathy. We hypothesize that removing these microparticles from circulation could mitigate the TBI-induced secondary pathologies and improve outcomes. In this study, we investigated the role of Gas-6 (growth arrest-specific 6) as a scavenging factor for microparticles.</p><p><strong>Methods: </strong>We quantified plasma Gas-6 levels in a mouse model of TBI and administered exogenous Gas-6 either before or after TBI to evaluate its effects on endotheliopathy, coagulopathy, and outcomes. Mechanistic studies assessed Gas-6-mediated clearance of circulating microparticles in TBI mice and investigated the molecular interactions by which Gas-6 binds microparticles and macrophages to facilitate microparticle scavenging.</p><p><strong>Results: </strong>We found that plasma levels of Gas-6 were significantly reduced in mice subjected to severe TBI. Exogenous Gas-6 given either preinjury or postinjury attenuated coagulopathy, protected the integrity of the cerebral and pulmonary endothelium, improved neurological recovery, and increased overall survival of TBI mice. Gas-6 increased the clearance of anionic phospholipid-expressing microparticles from circulation by coupling microparticles with macrophages and monocytes through the γ-carboxyglutamate and the LG1 (laminin G-like domain 1), respectively, to facilitate phagocytosis of microparticles in the liver.</p><p><strong>Conclusions: </strong>These findings demonstrate the therapeutic potential of Gas-6 for TBI and potentially for other acute pathologies, in which microparticles initiate and propagate coagulation dysfunction and endothelial injuries.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324955"},"PeriodicalIF":8.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677013","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}