Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"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":"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":"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":"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":"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}

{"title":"BAD-Glucokinase Axis Regulates Platelet Activation and Thrombosis.","authors":"Mengnan Yang, Shuang Chen, Qing Li, Kangxi Zhou, Yu Li, Chenglin Sun, Yue Xia, Jing Tan, Qiuxia Huang, Yuxin Jin, Renping Hu, Changgeng Ruan, Kesheng Dai, Rong Yan","doi":"10.1161/ATVBAHA.124.321738","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321738","url":null,"abstract":"<p><strong>Background: </strong>BAD (Bcl2-associated death promoter), a member of the Bcl2 proapoptotic family, promotes cell apoptosis by sequestering the prosurvival proteins Bcl-XL and Bcl2 from the proapoptotic proteins BAK and BAX in nucleated cells. BAD is also expressed in platelets, playing a role in regulating platelet lifespan, apoptosis, and clearance. However, whether BAD regulates platelet activation and arterial thrombosis remains unclear.</p><p><strong>Methods: </strong>The role of BAD in platelet activation and arterial thrombosis was investigated using BAD-deficient mice (<i>Bad</i>^<i>-/-</i>), in vitro functional studies, and arterial thrombosis models. The regulatory effect of BAD on platelet energy metabolism was detected using a Seahorse Extracellular Flux Analyzer. The regulatory effect of BAD on glucokinase was investigated by coimmunoprecipitation and activity measurement. The glucokinase heterozygous knockout mice (<i>Gck</i>^<i>+/-</i>) and activator were used to study its role in platelet activation.</p><p><strong>Results: </strong>BAD-deficient mice (<i>Bad</i>^<i>-/-</i>) and wild-type mice transfused with <i>Bad</i>^<i>-/-</i> platelets displayed prolonged tail bleeding and arterial occlusion times. <i>Bad</i>^<i>-/-</i> platelets exhibited decreased aggregation in response to stimulations by proteinase-activated receptor 4-activating peptide, thrombin, and U46619. Furthermore, BAD ablation suppressed platelet integrin α_IIbβ₃ activation, granule secretion, and clot retraction induced by these agonists. Mechanistically, BAD interacted with glucokinase, and BAD deficiency resulted in decreased platelet glucokinase activity, mitochondrial oxidative phosphorylation, and mitochondrial ATP production. The partial loss of glucokinase (<i>Gck</i>^<i>+/-</i>) phenocopied platelet function defects caused by BAD deficiency, and a glucokinase activator rescued the impaired mitochondrial ATP production and function of <i>Bad</i>^<i>-/-</i> platelets. Additionally, the glucokinase activator enhanced human platelet activation.</p><p><strong>Conclusions: </strong>Our findings demonstrate the critical role of the BAD-glucokinase axis in platelet activation and thrombosis, suggesting a potential target for antithrombotic therapy.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662002","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":"Chemokine (C-C Motif) Ligand 2 Expressing Adventitial Fibroblast Expansion During Loeys-Dietz Syndrome Aortic Aneurysm Formation.","authors":"Alex R Dalal, Albert J Pedroza, Jennifer Kim, Casey Gilles, Wenduo Gu, Sho Kusadokoro, Rohan Shad, Olivia Mitchel, William Jackson, William Hiesinger, Gerald Berry, Elena Gallo MacFarlane, Thomas Quertermous, Paul Cheng, Michael P Fischbein","doi":"10.1161/ATVBAHA.124.322069","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.322069","url":null,"abstract":"<p><strong>Background: </strong>Loeys-Dietz syndrome (LDS), caused by mutations in the TGF-β (transforming growth factor-β) signaling cascade, leads to aggressive thoracic aneurysms. While vascular smooth muscle cell (SMC) phenotype modulation has been implicated in thoracic aneurysm formation, we sought to characterize the role of cell state transitions in LDS aneurysm pathogenesis.</p><p><strong>Methods: </strong>We performed single-cell transcriptomic characterization of aortic root/ascending aorta from a murine LDS model (<i>Tgfbr2</i>^{<i>G357W/+</i>} versus littermate WT [wild-type] control) at 8 weeks, 24 weeks, and aortic root/ascending aortic samples from human LDS surgical specimens (n=5 LDS [<i>TGFBR1/2</i>] and n=2 donor control) to understand cell state transitions and transcriptomic alterations in LDS. Select cell markers were spatially localized with RNA in situ hybridization, immunofluorescence, and immunohistochemistry. Single-cell RNA sequencing of murine and human LDS samples (>30 000 cells) revealed unique SMC, fibroblast, and macrophage transcriptomic profiles in LDS.</p><p><strong>Results: </strong>Instead of SMC phenotypic modulation seen in Marfan syndrome, transcriptomic alterations observed in LDS are most prominent in the adventitial fibroblast in the <i>Tgfbr2</i>^{<i>G357W/+</i>} mouse model. While a distinct modulated SMC cluster does not appear in <i>Tgfbr2</i>^{<i>G357W/+</i>}, SMCs transcriptomically differ from WT counterparts. Adventitial fibroblasts were activated into a proinflammatory state associated with increased macrophage recruitment (<i>Ccl2</i>, <i>Il6</i>, <i>Ccl7</i>, and <i>Cxcl2</i>) and fibrotic response genes (<i>Col1a1</i>, <i>Col1a2</i>, and <i>Col3a1</i>), with a 6-fold increase in aortic wall macrophage content in <i>Tgfbr2</i>^{<i>G357W/+</i>} compared with WT. Similar findings were also observed in human LDS aortic samples with increased proinflammatory adventitial fibroblast transcriptomic program in parallel with heightened macrophage recruitment.</p><p><strong>Conclusions: </strong>Despite phenotypic similarities in aneurysm formation, the dominant cellular and molecular mechanism of Marfan syndrome and LDS aneurysms are distinct. LDS mouse and human adventitial fibroblasts transcriptomically modulate into a proinflammatory state. Adventitial fibroblasts, in addition to SMCs, are another important pathological cell population during LDS aneurysm formation to consider for targeted therapy to potentially impede LDS aneurysm formation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662003","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":"Is IDOL an Ideal Target for Treating Atherosclerosis?","authors":"Liyuan Zhu, Hong S Lu, Alan Daugherty","doi":"10.1161/ATVBAHA.125.322661","DOIUrl":"10.1161/ATVBAHA.125.322661","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662055","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":"Reconstituted High-Density Lipoproteins Rescue Diabetes-Impaired Endothelial Cell Metabolic Reprograming and Angiogenic Responses to Hypoxia.","authors":"Khalia R Primer, Joanne T M Tan, Lauren Sandeman, Victoria A Nankivell, Liam G Stretton, Emma L Solly, Peter J Psaltis, Christina A Bursill","doi":"10.1161/ATVBAHA.124.320110","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.320110","url":null,"abstract":"<p><strong>Background: </strong>Impaired angiogenic responses to ischemia underlie diabetic vascular complications. Reconstituted high-density lipoproteins (rHDLs) have proangiogenic effects in diabetes. The PDK4 (pyruvate dehydrogenase kinase 4)/PDC (pyruvate dehydrogenase complex) axis is an oxygen-conserving mechanism that preserves endothelial cell function in hypoxia. We aimed to determine the role of the PDK4/PDC axis in angiogenesis, the effect of diabetes on its regulation in response to ischemia, and the proangiogenic properties of rHDL.</p><p><strong>Methods: </strong>Expression of PDK4 and phosphorylated PDC (pPDC) were measured in PBS- or rHDL-treated wounds of nondiabetic and streptozotocin-induced diabetic mice and PBS- or rHDL-treated endothelial cells exposed to glucose and hypoxia. The importance of PDK4 in the action of rHDL was determined by siRNA knockdown in vitro and PDK4 inhibitor in vivo. Chromatin immunoprecipitation assay was performed to identify the mechanism for PDK4 induction by rHDL.</p><p><strong>Results: </strong>PDK4 and pPDC were elevated early (24 hours) post-induction of wound ischemia in nondiabetic wounds, which did not occur in diabetic mice. Topical rHDL rescued this impairment, enhancing PDK4 (68%; <i>P</i>=0.0041) and pPDC (165%; <i>P</i>=0.029) in diabetic wounds. Wound neovascularization (62%; <i>P</i><0.05) and closure (154%; <i>P</i><0.001) were increased in diabetic rHDL-treated wounds. In vitro, PDK4 and pPDC levels were increased with hypoxia (65%, <i>P</i>=0.043 and 64%, <i>P</i>=0.026, respectively). High glucose did not elicit a further stepwise induction in PDK4/pPDC, with aberrant increases in mitochondrial respiration (19%; <i>P</i>=0.026), and impaired angiogenic functions. Importantly, rHDL increased PDK4 and pPDC 2-fold, returning mitochondrial respiration and angiogenic functions to normal glucose levels. PDK4 inhibition ameliorated the proangiogenic effects of rHDL. rHDL increased FOXO1 (forkhead box O1) binding to the PDK4 promoter and suppressed FOXO1 phosphorylation, presenting FOXO1 as a mechanism for rHDL-mediated induction of PDK4.</p><p><strong>Conclusions: </strong>The PDK4/PDC axis response to ischemia is impaired in diabetes and is important for the proangiogenic effects of rHDL.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662127","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}