Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"TRPV4 Promotes Vascular Calcification by Directly Associating With and Activating β-Catenin.","authors":"Menglu Yuan, Qi Li, Zhiwei Wang, Liangju Liu, Chengyuan Wen, Guizhu Liu, Fan Yu, Lei Feng, Liu Yang","doi":"10.1161/ATVBAHA.124.321793","DOIUrl":"10.1161/ATVBAHA.124.321793","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification contributes to increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. Currently, there are no effective therapeutic strategies to prevent or reverse vascular calcification. TRPV4 (transient receptor potential channel V4), a key Ca²⁺-permeable channel, plays an important role in various diseases. However, the role and mechanism of TRPV4 in vascular calcification have not yet been elucidated.</p><p><strong>Methods: </strong>The effects of TRPV4 on vascular calcification were explored in vitro and in vivo. TRPV4 interactome assessment and molecular docking were performed to investigate the mechanism and specific therapeutic strategy for vascular calcification.</p><p><strong>Results: </strong>TRPV4 was substantially upregulated in high inorganic phosphate-induced calcified vascular smooth muscle cells (SMCs) and calcified aortas from cholecalciferol (vitamin D3)-overloaded mice. TRPV4 overexpression increased the expression of the osteochondrogenic markers Runx2 (runt-related transcription factor 2), Msx2 (Msh homeobox 2), and Sox9 (SRY-box transcription factor 9) and exacerbated high inorganic phosphate-induced vascular SMC calcification in a Ca²⁺ influx-dependent manner. In contrast, TRPV4 deficiency or inactivation significantly inhibited vascular SMC calcification under high inorganic phosphate conditions. Moreover, compared with that in control littermates, SMC-specific TRPV4 deficiency in mice alleviated vitamin D3-induced and 5/6 nephrectomy-induced vascular calcification. Mechanistically, TRPV4 interacted with β-catenin and activated β-catenin/TCF (T-cell factor) transcriptional activity via Ca²⁺/ASK1 (apoptosis signal regulating kinase 1)/p38 signaling. β-Catenin knockdown abolished the effects of TRPV4 overexpression on vascular SMC calcification. TRPV4/β-catenin interaction is pivotal for maintaining TRPV4/Ca²⁺-induced ASK1/p38/β-catenin activation. Hesperidin, a natural product found in citrus fruits, effectively disrupted TRPV4/β-catenin interaction, thereby inhibiting ASK1/p38/β-catenin activity and preventing vascular calcification.</p><p><strong>Conclusions: </strong>Our study identified TRPV4 as a new pathogenic factor for vascular calcification that directly associates with and activates β-catenin. Blocking the TRPV4/β-catenin interaction through hesperidin suppressed the progression of vascular calcification and may be an effective precision strategy to address vascular calcification.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e101-e117"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456725","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: High-Density Lipoprotein Lipid and Protein Cargo and Cholesterol Efflux Capacity Before and After Bariatric Surgery.","authors":"","doi":"10.1161/ATV.0000000000000184","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000184","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 4","pages":"e163"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727590","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":"ApoM and Major Adverse Cardiovascular Events in Chronic Kidney Disease: A Prospective Cohort Study.","authors":"Julia T Stadler, Andrea Borenich, Line Stattau Bisgaard, Sasha S Bjergfelt, Sarunja Vijayakumar, Line Melholt, Insa E Emrich, Ditte Hansen, Susanne Bro, Christina Christoffersen, Gunnar H Heine, Gunther Marsche","doi":"10.1161/ATVBAHA.124.322367","DOIUrl":"10.1161/ATVBAHA.124.322367","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease is the leading cause of mortality in patients with chronic kidney disease (CKD). APOM plays a critical role in reverse cholesterol transport by facilitating the formation of pre-β-HDL (high-density lipoprotein) and enabling the binding of S1P (sphingosine-1-phosphate) to HDL, a complex involved in several antiatherogenic processes. In this study, we sought to investigate the potential association between plasma APOM levels and the risk of adverse cardiovascular outcomes in individuals with CKD.</p><p><strong>Methods: </strong>Plasma APOM levels were quantified using a sandwich ELISA-based assay. Plasma S1P levels were measured by high-performance liquid chromatography. The primary end point was a composite of major adverse cardiovascular events (MACE) and all-cause mortality.</p><p><strong>Results: </strong>In this secondary analysis of the CARE FOR HOMe study (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation), 463 nondialysis patients with CKD stages G2 to G4 were included. Plasma APOM levels exhibited a significant inverse association with the risk of MACE (standardized hazard ratio, 0.60 [95% CI, 0.49-0.75]; <i>P</i><0.001) and all-cause mortality (standardized hazard ratio, 0.63 [95% CI, 0.48-0.83]; <i>P</i><0.001). This inverse association with MACE remained robust after adjusting for established cardiovascular and renal risk factors. These findings were further corroborated in an independent cohort of 822 patients with CKD from the Copenhagen CKD study. Plasma S1P levels showed an inverse association with MACE in univariable analyses; however, this relationship lost statistical significance after multivariable adjustments.</p><p><strong>Conclusions: </strong>Our findings demonstrate a significant association between low plasma APOM levels and an increased risk of MACE in patients with CKD. These results suggest that APOM may play a role in cardiovascular protection in this vulnerable population.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"496-505"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565823","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":"Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice.","authors":"Yang Zhou, Dong Wang, Juhong Wu, Yingying Qi, Meiru Song, Huiqiao Yao, Christopher Kai Liao, Haili Lin, Meijuan Huang, Dexiang Zhuo, Longguang Jiang, Cai Yuan, Yuanzhong Chen, Mingdong Huang, Jinyu Li, Peng Xu","doi":"10.1161/ATVBAHA.124.322145","DOIUrl":"10.1161/ATVBAHA.124.322145","url":null,"abstract":"<p><strong>Background: </strong>FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.</p><p><strong>Methods: </strong>A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI^-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.</p><p><strong>Results: </strong>Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (half maximal inhibitory concentration of 0.17 μmol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI^-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.</p><p><strong>Conclusions: </strong>This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e150-e162"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514545","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":"Gut Microbial Metabolite Imidazole Propionate Impairs Endothelial Cell Function and Promotes the Development of Atherosclerosis.","authors":"Vanasa Nageswaran, Alba Carreras, Leander Reinshagen, Katharina R Beck, Jakob Steinfeldt, Marcus Henricsson, Pegah Ramezani Rad, Lisa Peters, Elisabeth T Strässler, Joseph Lim, Barbara Verhaar, Yvonne Döring, Christian Weber, Maximilian König, Elisabeth Steinhagen-Thiessen, Ilja Demuth, Nicolle Kränkel, David M Leistner, Michael Potente, Max Nieuwdorp, Petra Knaus, Wolfgang M Kuebler, Marc Ferrell, Ina Nemet, Stanley L Hazen, Ulf Landmesser, Fredrik Bäckhed, Arash Haghikia","doi":"10.1161/ATVBAHA.124.322346","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322346","url":null,"abstract":"<p><strong>Background: </strong>The microbially produced amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effects of ImP on endothelial cell (EC) physiology and its role in atherosclerotic coronary artery disease are unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis.</p><p><strong>Methods: </strong>Plasma levels of ImP were measured in patients undergoing elective cardiac angiography (n=831) by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios and corresponding 95% CIs for coronary artery disease were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. The effects of ImP on functional properties of ECs were assessed using human aortic ECs. In a mouse model of carotid artery injury, the impact of ImP on vascular regeneration was examined. Additionally, atheroprone <i>Apoe</i>^<i>-/-</i> mice fed a high-fat diet were treated with and without ImP (800 µg), and aortic atherosclerotic lesion area was evaluated after 12 weeks. Next-generation sequencing, Western blot analysis, small interfering RNA-based gene knockdown, and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms.</p><p><strong>Results: </strong>Plasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk of prevalent coronary artery disease. We found that ImP dose dependently impaired migratory and angiogenic properties of human ECs and promoted an increased inflammatory response. Long-term exposure to ImP compromised the repair potential of the endothelium after an arterial insult. In atheroprone <i>Apoe</i>^<i>-/-</i> mice, ImP increased atherosclerotic lesion size. Mechanistically, ImP attenuated insulin receptor signaling by suppressing the PI3K (phosphoinositide 3-kinase)/AKT pathway leading to sustained activation of the FOXO1 (forkhead box protein O1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of ECs after carotid injury.</p><p><strong>Conclusions: </strong>Our findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717822","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":"Choroidal Neovascularization Is Suppressed With Activation of TREM2 in Mononuclear Phagocytes.","authors":"Hitomi Yagi, Myriam Boeck, Katherine Neilsen, Jay Yang, Minji Ko, Yohei Tomita, Kazuno Negishi, Zhongjie Fu, Ye Sun, Lois E H Smith","doi":"10.1161/ATVBAHA.124.321809","DOIUrl":"10.1161/ATVBAHA.124.321809","url":null,"abstract":"<p><strong>Background: </strong>Mononuclear phagocytes contribute to pathological angiogenesis in age-related macular degeneration, a leading worldwide cause of visual impairment. However, the mechanisms that orchestrate the functions of mononuclear phagocytes remain poorly understood. TREM2 (triggering receptor on myeloid cells 2) has been shown to be crucial for the activation of mononuclear phagocytes in atherosclerosis, fatty liver disease, and Alzheimer disease. The objective of this study was to investigate the role of TREM2 in pathological angiogenesis in age-related macular degeneration.</p><p><strong>Methods: </strong>C57BL/6J and <i>Trem2</i> knockout mice were subjected to laser-induced choroidal neovascularization, a model of choroidal neovascular age-related macular degeneration. Purified bovine sulfatide and agonist anti-TREM2 antibody was used to activate TREM2 signaling. The expression of TREM2 or downstream signals were assessed with immunohistochemistry or qPCR. In vitro murine macrophage RAW264.7 cells were used to investigate the direct impact of sulfatide on inflammatory and phagocytic responses.</p><p><strong>Results: </strong>We found that pharmacological activation of TREM2 suppressed laser-induced choroidal neovessel formation. The activation of TREM2 in mononuclear phagocytes suppressed TNF (tumor necrosis factor) and subsequently promoted phagocytosis.</p><p><strong>Conclusions: </strong>These findings demonstrate that activation of TREM2 in mononuclear phagocytes suppresses the proinflammatory response, promotes phagocytosis, and impedes choroidal neovessel formation. Our study provides insight into the critical role of TREM2 in pathological angiogenesis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717820","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":"MrgD as a Novel Modeling and Treatment Target for Pulmonary Hypertension.","authors":"Hongyu Zhong, Lina Yao, Huailong An, Lijun Fang, Xiaolin Liu, Qianqian Wang, Qimou Li, Dongdong Liu, Cong Fan, Mei Zhang, Cheng Zhang, Yun Zhang, Panpan Hao","doi":"10.1161/ATVBAHA.124.322337","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322337","url":null,"abstract":"<p><strong>Background: </strong>The hyperproliferation of smooth muscle cells and deposition of collagen in the pulmonary artery are among the primary characteristics of pulmonary hypertension (PH). These processes contribute to vascular remodeling, ultimately leading to elevated pulmonary artery pressure and right ventricular failure. The MrgD (Mas-related G-protein-coupled receptor member D) exhibits close associations with certain cardiovascular diseases; however, its role in PH remains unclear.</p><p><strong>Methods: </strong>The effects of the absence or activation of MrgD on PH were investigated using PH animal models induced by Sugen5416+hypoxia, monocrotaline, as well as global or smooth muscle-specific knockout of MrgD. Signaling pathways regulated by MrgD were investigated using high-throughput screening of data from single-cell sequencing of mouse lungs and RNA sequencing of human pulmonary artery smooth muscle cells, as well as other molecular biology experiments.</p><p><strong>Results: </strong>We observed decreased MrgD levels in animal models and patients with PH. Both global and conditional knockout of MrgD exacerbated hypoxia-induced PH in mice. MrgD activation attenuated the PH phenotypes in several established models, although these protective effects were reversed in MrgD-knockout mice. Transcriptome analysis revealed a significantly differentially expressed protein, PIM1, as a potential MrgD target. Silencing MrgD increased pulmonary artery smooth muscle cell proliferation by facilitating the AKT-mediated interaction of MAZ with PIM1. MrgD activation inhibited this pathway and was ineffective in PH mice with pulmonary artery smooth muscle cells overexpressing PIM1.</p><p><strong>Conclusions: </strong>MrgD deficiency in pulmonary arterioles increases susceptibility to PH, particularly in a hypoxic environment. MrgD is a potential modeling and therapeutic target for PH.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717826","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":"9p21.3 Coronary Artery Disease Risk Locus Drives Vascular Smooth Muscle Cells to an Osteochondrogenic State.","authors":"Elsa Salido, Carolina de Medeiros Vieira, José Verdezoto Mosquera, Rohan Zade, Parth Parikh, Shraddha Suryavanshi, Clint L Miller, Valentina Lo Sardo","doi":"10.1161/ATVBAHA.124.322045","DOIUrl":"10.1161/ATVBAHA.124.322045","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies have identified common genetic variants at ≈300 human genomic loci linked to coronary artery disease susceptibility. Among these genomic regions, the most impactful is the 9p21.3 coronary artery disease risk locus, which spans a 60-kb gene desert and encompasses ≈80 SNPs in high linkage disequilibrium. Despite ≈2 decades since its discovery, the role of the 9p21.3 locus in cells of the vasculature remains incompletely resolved.</p><p><strong>Methods: </strong>We differentiated induced pluripotent stem cells from risk, nonrisk donors at 9p21.3, and isogenic knockouts into vascular smooth muscle cells (VSMCs). We performed single-cell transcriptomic profiling, including coembedding and comparison with publicly available human arterial data sets. We conducted functional characterization using migration and calcification assays and confirmed our findings on induced pluripotent stem cells-VSMCs derived from additional donors. Finally, we used overexpression of <i>ANRIL</i> followed by gene expression analysis.</p><p><strong>Results: </strong>We demonstrated that induced pluripotent stem cells-VSMCs harboring the 9p21.3 risk haplotype preferentially adopt an osteochondrogenic state and show remarkable similarity to fibrochondrocytes from human artery tissue. The transcriptional profile and functional assessment of migration and calcification capacity across induced pluripotent stem cell-VSMC lines from multiple donors concordantly resemble an osteochondrogenic state. Importantly, we identified numerous transcription factors driving different VSMC state trajectories. Additionally, we prioritized <i>LIMCH1</i> and <i>CRABP1</i> as signature genes critical for defining the risk transcriptional program. Finally, overexpression of a short isoform of <i>ANRIL</i> in 9p21.3 knockout cells was sufficient to induce the osteochondrogenic transcriptional signature.</p><p><strong>Conclusions: </strong>Our study provides new insights into the mechanism of the 9p21.3 risk locus and defines its previously undescribed role in driving a disease-prone transcriptional and functional state in VSMCs concordant with an osteochondrogenic-like state. Our data suggest that the 9p21.3 risk haplotype likely promotes arterial calcification, through altered expression of <i>ANRIL</i>, in a cell type-specific and cell-autonomous manner, providing insight into potential risk assessment and treatment for carriers.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717776","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":"Lymphatic Activation of ACKR3 Signaling Regulates Lymphatic Response After Ischemic Heart Injury.","authors":"Laszlo Balint, Shubhangi Patel, Donald Stephen Serafin, Hua Zhang, Kelsey E Quinn, Amir Aghajanian, Bryan M Kistner, Kathleen M Caron","doi":"10.1161/ATVBAHA.124.322288","DOIUrl":"10.1161/ATVBAHA.124.322288","url":null,"abstract":"<p><strong>Background: </strong>Ischemic heart disease is a prevalent cause of death and disability worldwide. Recent studies reported a rapid expansion of the cardiac lymphatic network upon ischemic heart injury and proposed that cardiac lymphatics may attenuate tissue edema and inflammatory mechanisms after ischemic heart injury. Nevertheless, the mechanisms through which hypoxic conditions affect cardiac lymphangiogenesis and function remain unclear. Here, we aimed to characterize the role of the AM (adrenomedullin) decoy receptor ACKR3 (atypical chemokine receptor-3) in the lymphatic response following ischemic heart injury.</p><p><strong>Methods: </strong>Spatial assessment of ACKR3 signaling in the heart after ischemic heart injury was conducted using ACKR3-Tango-GFP reporter mice. Roles of ACKR3 after ischemic heart injury were characterized in <i>Ackr3</i>^{<i>∆Lyve1</i>} mice and in cultured human lymphatic endothelial cells exposed to hypoxia.</p><p><strong>Results: </strong>Using the novel ACKR3-Tango-GFP reporter mice, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery ligation. <i>Ackr3</i>^{<i>∆Lyve1</i>} mice exhibited better survival after left anterior descending artery ligation, especially within the first couple of days post-injury, and were protected from the formation of acute tissue edema. <i>Ackr3</i>^{<i>∆Lyve1</i>} mice exhibited a denser cardiac lymphatic network after left anterior descending artery ligation, especially in the injured tissues. Transcriptomic analysis revealed changes in cardiac lymphatic gene expression patterns that have been associated with extracellular matrix remodeling and immune activation. We also found that ACKR3 plays a critical role in regulating continuous cell-cell junction dynamics in lymphatic endothelial cells under hypoxic conditions.</p><p><strong>Conclusions: </strong>Lymphatic expression of ACKR3 governs numerous processes following ischemic heart injury, including the lymphangiogenic response, edema protection, and overall survival. These results expand our understanding of how the heart failure biomarker AM, regulated by lymphatic ACKR3, may exert its roles after ischemic cardiac injury.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717824","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":"PA System in the Pathogenesis of Ischemic Stroke.","authors":"Boxin Zhang, Lisa Leung, Enming J Su, Daniel A Lawrence","doi":"10.1161/ATVBAHA.125.322422","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.322422","url":null,"abstract":"<p><p>Ischemic stroke remains a leading cause of morbidity and mortality worldwide, driven by complex pathophysiological mechanisms that make finding effective treatments challenging. PAs (plasminogen activators) play a critical role in fibrinolysis and vascular homeostasis and as such are important factors affecting stroke outcome. This review examines the complex relationships between ischemic stroke and PAs, highlighting their physiological, pathological, and therapeutic effects on ischemic stroke. We focus on recombinant tissue-type PA as the only Food and Drug Administration-approved thrombolytic agent, describing its clinical impact and associated obstacles impacting its wide-scale use, such as blood-brain barrier disruption and inflammation. Furthermore, emerging PA-based therapies and combination strategies are explored to address the limitations of recombinant tissue-type PA. By integrating mechanistic information with clinical developments, this review aims to provide insights for the advancement of PA-centered approaches to improve the safety and efficacy of stroke treatments.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717829","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}