Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Spleen Tyrosine Kinase Inhibition Mitigates Hemin-Induced Thromboinflammation in an Organ-Specific Manner in Sickle Cell Mice.","authors":"Juma El-Awaisi, Gina Perrella, Nicolas Mayor, Veronika Tinkova, Simon J Cleary, Beata Grygielska, Steve P Watson, Jordan D Dimitrov, Alexander Brill, Eman Hassan, Phillip L R Nicolson, Dean Kavanagh, Neena Kalia, Julie Rayes","doi":"10.1161/ATVBAHA.124.322072","DOIUrl":"10.1161/ATVBAHA.124.322072","url":null,"abstract":"<p><strong>Background: </strong>Sickle cell disease (SCD) is a challenging genetic disorder characterized by hemolytic anemia, vaso-occlusive crises (VOC), and progressive organ damage. Despite its severity, effective treatments are limited. The recent withdrawal of promising therapies, such as the anti-P-selectin antibody Crizanlizumab and the hemoglobin polymerization inhibitor Voxelotor, highlights the urgent need for innovative approaches to alleviate vaso-occlusion and thromboinflammation.</p><p><strong>Methods: </strong>In this study, we used advanced techniques, including intravital microscopy, laser speckle contrast imaging, and histological analysis, to examine the role of syk (spleen tyrosine kinase) in platelet and neutrophil recruitment, and blood perfusion in the lung, kidney, liver, and spleen of SCD mice.</p><p><strong>Results: </strong>In the Berkeley SCD model, hemin-induced vaso-occlusion and impairment in pulmonary blood perfusion were independent of red cell congestion and fibrin deposition. Hypoperfusion was driven by adhesion of neutrophils and platelets in the microcirculation and exacerbated by pulmonary emboli. Hemin-induced cell adhesion and hypoperfusion were also observed in the renal microcirculation, whereas it was limited in the liver and spleen of SCD mice, suggesting that organ-specific mechanisms drive hypoperfusion and vaso-occlusion. To explore therapeutic options, we investigated the potential of Syk inhibition in improving blood perfusion and reducing thrombo-inflammation in different organs. Selective Syk inhibition, using BI-1002494, reduced cellular adhesion in the pulmonary and renal microvasculature, effectively restoring blood perfusion and reducing thrombo-inflammation. Low-dose Syk inhibitor was effective in reducing neutrophil adhesion and improving blood perfusion without inducing bleeding. Increasing the dose exacerbated hemin-induced bleeding in the lungs, likely due to off-target activity againt other kinases, including Src.</p><p><strong>Conclusions: </strong>These findings underscore the critical role of Syk in platelet and neutrophil mediated-thrombo-inflammation and hypoperfusion in SCD, suggesting that Syk inhibition is a promising strategy to reduce organ-specific vaso-occlusion, improve renal and pulmonary perfusion, and reduce organ damage.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e483-e496"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858769","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":"ANGPTL4 Prevents Atherosclerosis by Preserving KLF2 to Suppress EndMT and Mitigates Endothelial Dysfunction.","authors":"Dong Im Cho, Joon Ho Ahn, Bo Gyeong Kang, InJoo Hwang, Hyang Hee Cho, Ju Hee Jun, Jin Yoo, Meeyoung Cho, Soo Ji Yoo, Hyung-Seok Kim, Yong Sook Kim, Youngkeun Ahn","doi":"10.1161/ATVBAHA.125.322700","DOIUrl":"10.1161/ATVBAHA.125.322700","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear.</p><p><strong>Methods: </strong>We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using <i>Apoe</i>^<i>-</i><i>/</i>^<i>-</i> mice, human umbilical vein endothelial cells, human aortic endothelial cells, and induced pluripotent stem cell-derived endothelial cells. EndMT features were also evaluated in human atherosclerotic plaques. In patients with coronary artery disease, we analyzed plasma ANGPTL4 levels in relation to coronary microvascular dysfunction, as assessed by coronary flow reserve and the index of microcirculatory resistance.</p><p><strong>Results: </strong>ANGPTL4 suppressed TNF-α (tumor necrosis factor alpha)-induced and IL-1β (interleukin-1 beta)-induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-β (transforming growth factor-β)-driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-β-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Krüppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction.</p><p><strong>Conclusions: </strong>These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-β-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1742-1761"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844302","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":"Genome-Wide Pleiotropy Analysis Identifies Shared and Opposing Pathways Influencing Coronary Artery Disease and Cancer.","authors":"James Yarmolinsky, Evelyn Lau, Fotios Koskeridis, Marc J Gunter, Dennis Wang, Abbas Dehghan, Ioanna Tzoulaki","doi":"10.1161/ATVBAHA.125.322433","DOIUrl":"10.1161/ATVBAHA.125.322433","url":null,"abstract":"<p><strong>Background: </strong>Coronary artery disease (CAD) and cancer are 2 leading global causes of mortality, with shared modifiable risk factors, yet the genetic and molecular mechanisms underlying their comorbidity remain poorly understood.</p><p><strong>Methods: </strong>We performed a genome-wide pleiotropy analysis to identify shared genetic mechanisms across CAD and 4 common cancers that share modifiable risk factors with CAD (breast, colorectal, lung, prostate).</p><p><strong>Results: </strong>Using genome-wide pleiotropy and colocalization analysis, we identified 60 colocalized susceptibility loci shared by CAD and site-specific cancer, of which 43 are novel, including loci at <i>TERT</i>, <i>MYO9B</i>, and <i>SREBF1</i>. For 35 loci, the lead SNP (single-nucleotide polymorphism) exhibited opposing effects on CAD and cancer risk. Gene-set enrichment analysis revealed distinct enrichment patterns of same-direction and opposing-direction pleiotropic loci, including differential associations with blood pressure-related traits, blood cell traits, and waist circumference. By integrating transcriptomic and proteomic data in multitrait colocalization, 13 pleiotropic loci influenced CAD and cancer risk via differential gene or protein expression of neighboring genes, including <i>CALCRL</i>, <i>ANGPTL4</i>, and <i>LAMC1</i>, targets of approved or investigational medications. Phenome-wide association analysis in the UK Biobank identified 1955 associations (false discovery rate [FDR] <i>P</i><0.05) of lead SNPs at multitrait colocalized loci with serum biomarkers and clinical measures, with apoA, HDL (high-density lipoprotein) cholesterol, and creatinine being associated with the largest number of lead SNPs.</p><p><strong>Conclusions: </strong>Our findings highlight shared and opposing genetic loci between CAD and cancer and provide insight into molecular intermediates mediating joint disease risk. Importantly, they indicate potential drug repurposing opportunities for dual CAD and cancer prevention while highlighting possible adverse and divergent effects of existing medications across both conditions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1945-1956"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940291","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":"Genomic Insights at the Maternal-Fetal Interface: Preeclampsia Subtypes and Clinical Implications.","authors":"Ido Solt, Omri Dominsky, Chen Ben David, Inbal Admati, Sarah M Cohen, Simcha Yagel","doi":"10.1161/ATVBAHA.125.321710","DOIUrl":"10.1161/ATVBAHA.125.321710","url":null,"abstract":"<p><p>Recent advances in single-cell transcriptomics have provided significant insights into the pathophysiology of preeclampsia, uncovering cell-type-specific gene expression changes at the maternal-fetal interface. Key discoveries include dysregulated angiogenic factors, such as elevated sFlt-1 (soluble fms-like tyrosine kinase-1) and reduced PlGF (placental growth factor), predominantly in syncytiotrophoblasts, alongside inflammatory and stress-related signatures in stromal and immune cells. These findings reinforce the clinically observed concept of 2 distinct preeclampsia subtypes: a placenta-dominant form and a maternal cardiovascular-dominant form, each characterized by unique etiologies, clinical presentations, and therapeutic implications. Ongoing genomic research has the potential to identify novel biomarkers and therapeutic targets, paving the way for improved screening and management strategies for this multifaceted condition.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1724-1731"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940339","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":"NAMPT Is A Novel Inhibitor of Vascular Calcification in Chronic Kidney Disease.","authors":"Qianqian Dong, Lihe Lu, Xiuli Zhang, Liyun Feng, Li Li, Hao Liu, An Chen, Zirong Lan, Yuanzhi Ye, Jiahui Zhu, Xiaoyu Liu, Yining Li, Qingchun Liang, Jianyun Yan","doi":"10.1161/ATVBAHA.125.322549","DOIUrl":"10.1161/ATVBAHA.125.322549","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is very common in patients with chronic kidney disease and contributes to the increased risk of cardiovascular events. NAMPT (nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide, has been shown to exert an antiaging effect on vascular smooth muscle cells. However, whether NAMPT is involved in the regulation of vascular calcification remains unclear.</p><p><strong>Methods: </strong>ELISA, immunofluorescence, and Western blot were used to detect NAMPT levels in human blood and tissues. Alizarin red staining, calcium content assay, and microcomputed tomography were used to investigate the role of NAMPT in vascular calcification. Gene expression analysis and coimmunoprecipitation were performed to elucidate the underlying mechanism.</p><p><strong>Results: </strong>ELISA, immunofluorescence, and Western blot showed that NAMPT levels were increased in the blood of patients with chronic kidney disease and human calcified arterial tissues. Alizarin red staining and calcium content assay revealed that pharmacological inhibition or knockdown of NAMPT exacerbated vascular smooth muscle cell calcification, whereas overexpression of NAMPT reduced mineral deposition under osteogenic conditions. Similarly, ex vivo studies revealed that NAMPT inhibited calcification of rat and human arterial rings. Moreover, administration of NAMPT inhibitor FK866 promoted aortic calcification of chronic kidney disease rats, and smooth muscle cell-specific NAMPT knockout mice exhibited aggravated aortic calcification. Furthermore, pharmacological inhibition and knockdown of SIRT1 (sirtuin 1) abrogated the inhibitory effect of NAMPT on vascular calcification. In addition, smooth muscle cell-specific SIRT1 deficiency abrogated the protective effect of recombinant NAMPT on mouse aortic calcification. Coimmunoprecipitation and immunofluorescence assay further revealed that NAMPT inhibited the acetylation of NICD (Notch intracellular domain) and reduced the expression of HES1 (hairy and enhancer of split-1) in a SIRT1-dependent pathway.</p><p><strong>Conclusions: </strong>Our study unveils that NAMPT could serve as a novel endogenous inhibitor of vascular calcification via modulation of SIRT1-mediated deacetylation of NICD.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1872-1892"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991556","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":"Association Between Thrombus Signal Intensity and Pulmonary Embolism in Patients With Proximal Deep Vein Thrombosis: A Magnetic Resonance Imaging Study.","authors":"Xinyu Wang, Congrui Sun, Yuehong Liu, Yichen Tang, Chen Zhang, Alto Stemmer, Jiajia Zhang, Guoxi Xie, Chunmin Li, Qi Yang","doi":"10.1161/ATVBAHA.125.322857","DOIUrl":"10.1161/ATVBAHA.125.322857","url":null,"abstract":"<p><strong>Background: </strong>Approximately 50% of deep vein thrombosis (DVT) occurrences in the lower extremity proximal veins are associated with pulmonary embolism (PE). The progression of proximal DVT is critical in PE development, as reflected by thrombus composition. Magnetic resonance black-blood thrombus imaging can identify venous thrombus components by displaying thrombus signal intensity variations. This study investigated the association between thrombus signal intensity and PE in patients with proximal DVT.</p><p><strong>Methods: </strong>A total of 126 patients with proximal DVT were recruited, and all underwent magnetic resonance black-blood thrombus imaging examination. The patients were divided into 2 groups: DVT-only and DVT with PE. The whole thrombus signal intensity ratio, proximal thrombus signal intensity ratio, distal thrombus signal intensity ratio, and thrombus volume were assessed. Histological analysis was performed to characterize the thrombus content. Logistic regression models were performed to evaluate the relationship between thrombus signal intensity and PE.</p><p><strong>Results: </strong>Of the 126 eligible patients, 73 (58%) patients were in the DVT with PE group. Both proximal thrombus signal intensity ratio and whole thrombus signal intensity ratio were lower in the DVT with PE group compared with the DVT-only group (1.92±0.54 versus 1.31±0.42, <i>P</i><0.001; 1.76±0.41 versus 1.62±0.36, <i>P</i>=0.034). The percentage of fibrin area (13.99±1.56% versus 7.51±1.25%, <i>P</i>=0.0087) and red blood cells area (49.65±18.8% versus 13.41±4.74%, <i>P</i>=0.0012) were higher in DVT with PE than DVT-only group. Univariate and multivariate logistic regression analysis showed that proximal thrombus signal intensity ratio remained statistically significant (odds ratio, 0.21 [95% CI, 0.12-0.39]; <i>P</i><0.001).</p><p><strong>Conclusions: </strong>The proximal thrombus signal intensity ratio of the thrombus was independently associated with acute PE in patients with proximal lower extremity DVT, suggesting that thrombus components may be important in PE occurrence. These findings could provide novel insights for understanding DVT evolution.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1957-1968"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844303","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":"Immune Mechanisms of Vascular Disease in Preeclampsia.","authors":"Alice P Christensen, Serena Bert, Suchita Nadkarni","doi":"10.1161/ATVBAHA.124.321670","DOIUrl":"10.1161/ATVBAHA.124.321670","url":null,"abstract":"<p><p>Preeclampsia is a multisystem vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia affects 2% to 5% of pregnancies and is a major contributor to maternal and perinatal morbidity and mortality resulting from aberrant vascular and immunologic responses. While the exact mechanisms of why preeclampsia arises remain unclear, our current understanding suggests that inadequate vascular adaptations are a contributing factor to the disease. In this review, we focus on how immune system changes affect the onset and pathogenesis of preeclampsia, specifically in the context of placental vascular development and maternal cardiovascular dysfunction. We also discuss the potential direct link in preeclampsia between immune cells, inflammation, and how they impact placental vascular remodeling and maternal cardiac dysfunction.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1715-1723"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940312","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":"Effective Transcriptional Induction of the CARMN/miR-143/145 Complex Locus in Smooth Muscle Cells Using CRISPR Activation.","authors":"Francesca Vacante, Sandra Sanchez-Esteban, Themistoklis M Tsarouchas, Julie Rodor, Matthew Bennett, Melissa S Carroll, Abdelaziz Beqqali, Andrew H Baker","doi":"10.1161/ATVBAHA.124.322353","DOIUrl":"10.1161/ATVBAHA.124.322353","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1969-1971"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12453091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752159","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":"CXCL4-Induced PBMCs Modulate Vascular Extracellular Matrix via Wnt5a-Dependent Matrix Metalloproteinase-7 and Calcifying Extracellular Vesicle Release.","authors":"Jona B Krohn, Laurine Kristin Sprehe, Florian Sicklinger, Julie Kawohl, Chiara Hess, Anja Spieler, Susanne Dihlmann, Larissa Eis, Christian A Gleissner, Hugo A Katus, Norbert Frey, Florian Leuschner","doi":"10.1161/ATVBAHA.124.322067","DOIUrl":"10.1161/ATVBAHA.124.322067","url":null,"abstract":"<p><strong>Background: </strong>The role of macrophage heterogeneity has become increasingly well-recognized in the study of vascular inflammatory responses. The CXCL4 (chemokine [C-X-C motif] ligand 4)-induced monocyte/macrophage phenotype has been implicated in atherosclerotic plaque destabilization, a key process preceding plaque rupture. Monocyte-derived macrophages differentiated with CXCL4 exhibit a unique transcriptome characterized by upregulation of S100A8 (S100 calcium-binding protein A8/calgranulin A) and MMP7 (matrix metalloproteinase-7). However, the mechanisms involved in CXCL4-induced monocyte-mediated vascular inflammation are unknown.</p><p><strong>Methods: </strong>Single-cell RNA sequencing data were examined for CXCL4-dependent transcriptional signatures in plaque macrophages. Human peripheral blood-derived monocytes (PBMCs) differentiated with CXCL4 were characterized in terms of osteogenic signatures and calcifying extracellular vesicle (EV) release. Association of the CXCL4-induced phenotype with the Wnt (wingless-type) pathway was investigated, and CXCL4-induced PBMC-derived EV were analyzed for their calcification potential in ECM (extracellular matrix) hydrogels and their ability to elicit an inflammatory response in vascular smooth muscle cells. In vitro findings were verified histologically in human carotid artery plaques.</p><p><strong>Results: </strong>In human plaque macrophages, single-cell sequencing revealed a CXCL4-susceptible subpopulation bearing a distinct proinflammatory transcriptional signature. CXCL4-differentiated PBMCs exhibited a marked induction of S100A8, MMP7, and osteogenic marker transcription concomitant with augmented release of calcifying EV enriched with MMP7, S100A8, Anx5 (annexin 5), and ALP (alkaline phosphatase). Under osteogenic conditions, PBMCs and their secreted EV independently increased the calcification of the ECM in vitro. Analysis of inflammatory pathway activation identified the Wnt5a-CaMKII (wingless-type 5a-calcium/calmodulin-dependent protein kinase II) signaling axis to be linked to the CXCL4-induced osteogenic PBMC phenotype, EV calcification potential, and enrichment with MMP7 and S100A8. In addition, CXCL4-polarized PBMC-derived EV stimulated inflammatory gene expression in vascular smooth muscle cells. In human carotid artery plaques, CXCL4-induced macrophage abundance coincided with Wnt5a-CaMKII pathway activation and progressive plaque calcification.</p><p><strong>Conclusions: </strong>This study introduces a novel mechanism driving monocyte-mediated ECM remodeling in procalcific inflammatory responses through Wnt5a-CaMKII-activated secretion of MMP7⁺S100A8⁺ calcifying EV by CXCL4-induced proinflammatory monocytes.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1799-1817"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940328","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":"Directly Measuring Atherogenic Lipoprotein Kinetics in Zebrafish With the Photoconvertible LipoTimer Reporter.","authors":"Tabea O C Moll, Julia G Kiefer, Mackenzie L Klemek, Meredith H Wilson, Steven A Farber","doi":"10.1161/ATVBAHA.125.322969","DOIUrl":"10.1161/ATVBAHA.125.322969","url":null,"abstract":"<p><strong>Background: </strong>Lipoprotein kinetics are a crucial factor in understanding lipoprotein metabolism because a prolonged time in circulation can contribute to the atherogenic character of B-lps (ApoB-containing lipoproteins).</p><p><strong>Methods: </strong>We developed a genetically encoded B-Lp reporter, LipoTimer, in which the zebrafish endogenous <i>apoBb.1</i> (apolipoprotein Bb.1) gene was modified to produce a fusion with the photoconvertible fluorophore Dendra2, that shifts its emission profile from green to red on UV (ultraviolet radiation) exposure.</p><p><strong>Results: </strong>By quantifying the red population of ApoB-Dendra2 over time, we found that B-lp turnover in wild-type larvae becomes faster as development proceeds. Mutants with impaired B-lp uptake or lipolysis present with increased B-lp levels and half-life. In contrast, mutants with impaired B-lp triglyceride loading display slightly fewer and smaller B-lps, which have a significantly shorter B-lp half-life. Furthermore, we showed that chronic high-cholesterol feeding is associated with a longer B-lp half-life in wild-type juveniles but does not lead to changes in B-lp half-life in lipolysis-deficient <i>apoC2</i> (apolipoprotein C2) mutants. These data support the hypothesis that B-lp lipolysis is suppressed by the flood of intestinal-derived B-lps that follow a high-fat meal.</p><p><strong>Conclusions: </strong>In conclusion, the new LipoTimer reporter allows for direct in vivo examination of B-lp kinetics, which can be used to better understand the role of lipoprotein modifier genes and environmental factors (eg, diet) on B-lp lifetime.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1762-1783"},"PeriodicalIF":7.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940347","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}