Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Bioengineering Approaches for Nanomedicine Delivery in Therapy of Myocardial Infarction.","authors":"Jiawen Zou, Dashuai Zhu, Xiao Cheng, Ke Cheng","doi":"10.1161/ATVBAHA.126.324247","DOIUrl":"10.1161/ATVBAHA.126.324247","url":null,"abstract":"<p><p>Cardiovascular disease remains the leading cause of death globally. In particular, ischemic heart disease represents the most common condition in clinics. Adult hearts have minimal regenerative capacity. Upon myocardial infarction, the formation of activated myofibroblasts replaces the massive loss of cardiomyocytes. Nanomedicine has emerged as a promising strategy for cardiovascular disease treatment, with synthetic nanoparticles and extracellular vesicles serving as representative delivery platforms. However, directly applying these nanomedicines faces several challenges, including insufficient cardiac targeting, poor retention rate at the injured site, and potential biocompatibility concerns. To overcome these limitations, different bioengineering approaches have been adopted. In this review, we discussed the landscape of cardiovascular nanomedicine, encompassing both synthetic nanocarriers and biological carriers and targeted delivery. We further evaluated the engineering approaches to enhance carrier performance. Multiple administration routes are also compared. Collectively, these advances represent a shift toward an integrated, multifunctional delivery platform with the potential to translate cardiac nanomedicine from bench to bedside.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324247"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618309","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":"Endothelial Shear-Stress-Responsive Gene Adenylate Cyclase 4 Suppresses Atherosclerosis by Inhibiting cAMP/PKA-NF-κB Mediated Vascular Inflammation.","authors":"Wenzhen Bao, Jianfei Xu, Wenjian Nian, Peilin Pang, Wenrun Wu, Zijian Huang, Lin Hu, Hongda Li, Wenqi Pan, Xiaotong Gao, Weilin Hu, Lefeng Qu, Lin Zhang, Xiaoli Chen, Jie Liu, Yuzhen Zhang","doi":"10.1161/ATVBAHA.126.324797","DOIUrl":"10.1161/ATVBAHA.126.324797","url":null,"abstract":"<p><strong>Background: </strong>Endothelial dysfunction is critical for the pathogenesis of atherosclerosis, particularly in arterial regions exposed to disturbed flow (DF). ADCY4 (adenylate cyclase 4) catalyzes the production of cAMP (cyclic adenosine monophosphate), a ubiquitous second messenger that regulates cellular and physiological processes. This study investigated <i>ADCY4</i> as a shear-stress-responsive gene in endothelial cells (ECs) for the regulation of vascular endothelial inflammation during atherogenesis.</p><p><strong>Methods: </strong>Integrated analysis of RNA sequencing data sets from human vascular ECs exposed to unidirectional flow or DF, and single-cell RNA-seq data from mouse partial ligation carotid arteries, was performed. ADCY4 expression was quantified in cultured ECs under various flow conditions. Nanoparticles carrying <i>Cdh5</i> promoter-driven CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) and <i>Adcy4</i>-specific guide RNA plasmids were used to achieve EC-specific <i>Adcy4</i> knockout in <i>ApoE</i>^<i>-/-</i> mice for atherogenesis studies.</p><p><strong>Results: </strong>ADCY4 was upregulated in ECs under unidirectional flow but downregulated under DF. We identified that KLF2 (Krüppel-like factor 2) directly bound to the <i>ADCY4</i> promoter and transcriptionally enhanced its expression in human aortic ECs. <i>ADCY4</i> knockdown in ECs under unidirectional flow increased proinflammatory gene expression and monocyte adhesion, whereas <i>ADCY4</i> overexpression under DF produced opposite changes. Further studies showed ADCY4 attenuated endothelial inflammation by inhibiting NF-κB (nuclear factor κB) signaling. We performed partial carotid ligation in the high-fat diet-fed <i>ApoE</i>^<i>-/-</i> mouse atherosclerosis model, demonstrating that EC-specific <i>Adcy4</i> knockout increased vascular endothelial inflammation and monocyte infiltration, thus promoting atherosclerotic plaque formation. Aggravated atherogenesis was also observed in EC-<i>Adcy4</i> knockout high-fat diet-fed <i>ApoE</i>^<i>-</i>^<i>/-</i> mice, with increased atherosclerotic lesions in en face aortas and aortic arches. Finally, semaglutide increased ADCY4 expression in human aortic ECs under DF and reduced vascular endothelial inflammation, monocyte accumulation, and atherosclerotic plaque formation. These beneficial effects were substantially impaired when EC ADCY4 was absent.</p><p><strong>Conclusions: </strong>ADCY4 regulation of the cAMP/PKA (protein kinase A)-NF-κB pathway in the endothelium advances our understanding of vascular inflammation in atherogenesis and provides opportunities for therapeutic intervention of atherosclerotic cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324797"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677018","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":"Two Roads to a Shunt: Distinct Endothelial Programs in SMAD4 and ALK1 Loss-of-Function Explain Hereditary Hemorrhagic Telangiectasia Syndrome Diversity.","authors":"Nicolas Baeyens","doi":"10.1161/ATVBAHA.126.325282","DOIUrl":"10.1161/ATVBAHA.126.325282","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325282"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676550","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":"Exploring the Role of Hypusine Signaling in Vascular Smooth Muscle Cells for Mitigating Restenosis in Coronary Artery Disease.","authors":"Yann Grobs, Sarah-Eve Lemay, Manon Mougin, Charlie Thberge, Magalie Boucher, Sandra Breuils-Bonnet, Sandra Martineau, Alice Bourgeois, Andreanne Pelletier, Maud Fillon, Jean Perron, François Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet","doi":"10.1161/ATVBAHA.126.324325","DOIUrl":"10.1161/ATVBAHA.126.324325","url":null,"abstract":"<p><strong>Background: </strong>Post-surgical restenosis in patients with coronary artery disease (CAD) is a pathological vascular remodeling process characterized by neointimal hyperplasia, which is mainly driven by phenotypic switching of vascular smooth muscle cells toward a synthetic and proliferative state. This study investigated a novel signaling pathway to promote the proproliferative phenotype of vascular smooth muscle cells and contribute to the neointimal hyperplasia development.</p><p><strong>Methods: </strong>Using comparative proteomic analysis and Western blotting, expression of hypusine signaling components was evaluated in human primary cultures of coronary artery smooth muscle cells isolated from controls and patients with CAD, as well as in 3 preclinical animal models of restenosis: rat carotid injury, mouse carotid ligation, and canine coronary artery bypass graft. CAD-coronary artery smooth muscle cell proliferation was assessed by Western blot and immunofluorescence with pharmacological (N1-guanyl-1,7-diaminoheptane) and molecular (shRNA) inhibitors of DHPS (deoxyhypusine synthase). The contribution of hypusine signaling to neointimal hyperplasia was investigated using both pharmacological and genetic approaches. In addition, human saphenous vein and human coronary artery tissue cultures were used to explore the translational potential of targeting hypusine signaling to prevent neointimal hyperplasia.</p><p><strong>Results: </strong>All components of the hypusine pathway (eIF5A (eukaryotic translation initiation factor 5A), DOHH (deoxyhypusine hydroxylase), and DHPS were significantly overexpressed in CAD-coronary artery smooth muscle cells and in preclinical animal models of restenosis. Pharmacological and molecular inhibition of DHPS reduced eIF5A hypusination, vascular smooth muscle cell proliferation, and expression of ECM (extracellular matrix) proteins. Proteomic and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses demonstrated disruption of cell-cycle and DNA replication pathways, including a downregulation of TTK (threonine tyrosine kinase). Our findings suggest that TTK acts as a downstream effector of hypusine signaling, which partly mediates the proliferative effects observed in CAD-coronary artery smooth muscle cells. In vivo, pharmacological and smooth muscle cell-targeted inactivation of DHPS significantly reduced neointimal hyperplasia without adverse effects. Finally, ex vivo human tissue culture confirmed that N1-guanyl-1,7-diaminoheptane mitigates growth factor-induced vascular remodeling.</p><p><strong>Conclusions: </strong>Hypusine signaling is a critical regulator of vascular smooth muscle cell proliferation for neointimal hyperplasia. Inhibiting DHPS reduces vascular remodeling, making it a promising target for preventing restenosis after coronary interventions.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324325"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366832","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":"Dual Lineage Tracing Identifies Cellular Mechanisms Underlying Radiation-Associated Changes in Atherosclerotic Lesion Composition-Brief Report.","authors":"Rebecca A Deaton, Tajbir Raihan, Victoria M Milosek, Fatema Allaham, Alexandra L Krinsky, Laura S Shankman, Alexander M Como, Gabriel F Alencar, Anita Salamon, Nazanin Moradinasab, Subhashis Banerjee, Gary K Owens","doi":"10.1161/ATVBAHA.126.324417","DOIUrl":"10.1161/ATVBAHA.126.324417","url":null,"abstract":"<p><strong>Background: </strong>Phenotypic plasticity of smooth muscle cells (SMCs) and endothelial cells (ECs) contributes to atherosclerotic plaque composition and stability, yet how shifts in one population influence the contribution and function of the other under conditions of vascular stress, such as irradiation, is poorly understood. A major limitation has been the inability to simultaneously fate-map both cell types within the same lesion, with most studies mapping one lineage while inferring the other using unreliable dynamically changing marker genes, risking false-positive and false-negative assignment.</p><p><strong>Methods: </strong>We generated dual lineage tracing <i>Apoe</i>-deficient mice, enabling simultaneous fate mapping of SMCs and ECs. This model was used to extend prior findings from single lineage tracing models demonstrating irradiation-induced loss of SMC lesion investment and expansion of EC-derived cells. Dual lineage tracing mice were subjected to irradiation followed by Western diet feeding to induce atherosclerosis. Lineage tracing, immunostaining, and single-cell RNA sequencing analysis were used to define coordinated SMC and EC responses and identify changes relevant to plaque instability.</p><p><strong>Results: </strong>Dual lineage tracing simultaneously labeled SMC- and EC-derived cells in healthy and atherosclerotic vessels. Irradiation induced divergent responses: SMC-derived cells failed to invest in lesions and upregulated stress-activated inflammatory genes, whereas EC-derived cells expanded and upregulated SMC-associated genes. However, EC-derived cells within lesions failed to induce extracellular matrix genes, and lesions from irradiated mice exhibited reduced collagen content and fewer ACTA2 (α-smooth muscle actin)⁺ cells within the fibrous cap, consistent with reduced plaque stability.</p><p><strong>Conclusions: </strong>Dual lineage tracing of SMCs and ECs demonstrated that irradiation-induced loss of lesional SMC and expansion of EC-derived ACTA2⁺ cells are not artifacts of false lineage assignment. By resolving SMC and EC fate within the same lesion, we identify irradiation-induced cell dynamics including inflammatory reprogramming of SMCs, EC phenotypic modulation, impaired extracellular matrix organization, and reduced ACTA2⁺ fibrous cap cellularity that may contribute to radiotherapy-associated increased atherosclerotic cardiovascular disease risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324417"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676937","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":"Gene-Specific Endothelial Programs Drive AVM Pathogenesis in <i>SMAD4</i> and <i>ALK1</i> Loss-of-Function.","authors":"Olya Oppenheim, Wolfgang Giese, Hyojin Park, Elisabeth Baumann, Andranik Ivanov, Dieter Beule, Anne Eichmann, Holger Gerhardt","doi":"10.1161/ATVBAHA.125.323908","DOIUrl":"10.1161/ATVBAHA.125.323908","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hemorrhagic telangiectasia is a genetic disorder caused by loss-of-function mutations in components of the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. Most prior work has treated BMP (bone morphogenetic protein) component depletion as mechanistically interchangeable, yet whether distinct genes converge on a shared mechanism remains unclear. We aimed to understand the molecular relationship between BMP signaling and endothelial flow response that leads to arteriovenous malformation formation.</p><p><strong>Methods: </strong>We expose human endothelial monolayers treated with small interfering RNA against <i>SMAD4</i> or <i>ALK1</i> to laminar flow and analyze flow-responsive transcriptomics, flow-responsive BMP signaling activation dynamics, cell polarity, and morphology. We analyze the cell-autonomous and noncell-autonomous migration dynamics of endothelial cells treated with <i>siSMAD4</i> or <i>siALK1</i>. Using the postnatal mouse retina model, we study endothelial cell distribution changes over time in mosaic settings, and assess the remodeling capabilities of <i>Smad4</i>^iECKO or <i>Alk1</i>^iECKO, relative to littermate controls.</p><p><strong>Results: </strong>This study shows that depletion of <i>SMAD4</i> or <i>ALK1</i> leads to fundamentally distinct mechanisms of vascular malformation. <i>SMAD4</i> deficiency enhances endothelial responses to blood flow, including transcriptional activation and migration against flow, causing excessive capillary pruning and the development of single large shunts. In contrast, <i>ALK1</i> deficiency disrupts flow sensing, impairs cell polarization and migration, and promotes a persistent angiogenic state, resulting in dense, hypervascularized networks. RNA sequencing across static and flow conditions identifies both flow-dependent and flow-independent transcriptional changes, suggesting early defects in endothelial fate specification. Mosaic in vitro models show that mutant cells co-opt neighboring wild-type cells, while in vivo tracking confirms mutation-specific migration behavior.</p><p><strong>Conclusions: </strong>These findings reveal divergent cellular programs driving arteriovenous malformations and underscore the need for gene-specific diagnostic and therapeutic strategies.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323908"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454352","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":"Olfactomedin-2 at the Crossroads of Smooth Muscle Cell Plasticity.","authors":"Adil Ijaz, Marco Orecchioni","doi":"10.1161/ATVBAHA.126.325262","DOIUrl":"10.1161/ATVBAHA.126.325262","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e325262"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13426069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560825","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":"Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36.","authors":"Mirza Ahmar Beg, Quoc Quang Luu, Vaya Chen, Yaxin Wang, Gang Xin, Weiguo Cui, Roy L Silverstein, Yiliang Chen","doi":"10.1161/ATVBAHA.126.324938","DOIUrl":"10.1161/ATVBAHA.126.324938","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Mφs (macrophages) significantly contribute to this process through their scavenger receptor CD36 (cluster of differentiation 36). PIM1 (proviral integration site for Moloney murine leukemia virus 1) is a serine/threonine kinase known to modulate immune responses and cell metabolism. However, its role in Mφ lipid handling and atherogenesis is not well defined. This study examines the role of PIM1 in regulating CD36 expression and function in Mφs during foam cell formation and atherosclerosis progression.</p><p><strong>Methods: </strong>We performed in vitro studies by treating murine peritoneal Mφs from <i>Pim1</i>^-/- and wild-type mice with oxLDL (oxidized low-density lipoprotein). We measured CD36, PIM1, and plaque-associated proteins and mRNA levels, oxLDL binding and uptake rates, and foam cell formation. For in vivo studies, we fed myeloid-specific <i>Pim1</i>-deficient (<i>Apoe</i>^-/-<i>Lyz2</i>^Cre/+<i>Pim1</i>^fl/fl) and their littermate control (<i>Apoe</i>^-/-<i>Pim1</i>^fl/fl) mice a high-fat diet for 12 weeks. We then evaluated plaque formation in their aortic sinuses and arches.</p><p><strong>Results: </strong>Deletion of <i>Pim1</i> in Mφs reduced CD36 protein expression by up to 96.7% compared with wild-type controls. This led to a 49.6% decrease in foam cell formation and a 25.5% reduction in cellular cholesterol after oxLDL treatment. Pharmacological inhibition of PIM kinase activity in wild-type Mφs also impaired oxLDL handling, with a 64.5% reduction in binding and a 57.9% reduction in uptake. Bulk RNA-sequencing revealed that <i>Pim1</i> deficiency downregulated PPARγ (peroxisome proliferator-activated receptor gamma) signaling. Treatment with a PPARγ agonist restored CD36 levels in the <i>Pim1</i> knockdown Mφs, suggesting that PIM1 regulates CD36 through PPARγ. Moreover, <i>Pim1</i> myeloid-specific deficiency caused a 69.4% reduction in atherosclerotic plaque formation.</p><p><strong>Conclusions: </strong>PIM1 acts as a key upstream regulator of CD36 by enhancing PPARγ activity in Mφs. The PIM1-CD36 axis promotes oxLDL binding, uptake, and foam cell formation. Targeting the PIM1/PPARγ/CD36 pathway could offer new ways to modulate Mφ lipid metabolism and reduce atherosclerotic plaque progression.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324938"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13464522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676465","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":"Adipose Tissue Immunosuppressive T Cells Regulate Atherosclerosis Development and Liver Fat Accumulation in Obesity.","authors":"Alecia M Blaszczak, Dharti Shantaram, Xilal Y Rima, Valerie P Wright, Joey Liu, Alan J Smith, Anahita Jalilvand, Anastasiia Amari, Chase D Bender, Dana Middendorf, Regina Gebhardt, Martha M Yearsley, Debasish Roy, Edward A Fisher, David Bradley, Willa A Hsueh","doi":"10.1161/ATVBAHA.125.324204","DOIUrl":"10.1161/ATVBAHA.125.324204","url":null,"abstract":"<p><strong>Background: </strong>Obesity is associated with a loss of anti-inflammatory regulatory T cells (Tregs) in adipose tissue (AT), resulting in systemic inflammation. The adipocyte is a central modulator of CD4+T-cell subpopulations via antigen presentation through the MHCII (major histocompatibility complex class II). However, the role of adipocyte-induced AT inflammation due to changes in AT Tregs in obesity-related complications, such as atherosclerosis and metabolic-dysfunction-associated fatty liver disease (MAFLD), remains unknown.</p><p><strong>Methods: </strong>Ldlr (low-density lipoprotein receptor)^-/- knockout mice were crossed with adipocyte-specific MHCII knockout (aMHCll [adipocyte MHCII]^-/-) mice to study the effects of AT T-cell changes on atherosclerosis and MAFLD. Metabolic differences, atherosclerotic lesions, liver fat accumulation, and inflammation in adipose, splenic, aortic, and liver tissue were measured in 1-year-old aMHCll^-/- Ldlr^-/- mice fed a Western high-fat diet for 12 weeks. We used 1-year-old mice because, unlike young mice, they develop markedly accelerated atherosclerosis like humans.</p><p><strong>Results: </strong>Loss of MHCII signaling in adipocytes prevented the obesity-mediated loss of AT Tregs, resulting in decreased insulin resistance, atherosclerosis, and MAFLD. In contrast, depletion of AT Tregs via IL (interleukin)-33 receptor-targeted immunotherapy with ST2 (suppression of tumorigenicity 2) reversed these improvements in Western high-fat diet-fed, 1-year-old aMHCll^-/- Ldlr^-/- mice, whereas increasing AT Tregs with IL-33 recombinant protein promoted similar beneficial effects as in aMHCll^-/- Ldlr^-/- mice. Because there were no alterations in splenic Tregs, these differences in atherosclerosis and MAFLD were AT Treg-mediated, independent of peripheral Tregs. Amelioration of insulin resistance, atherosclerosis, and MAFLD was diet- and adipocyte-dependent, as a low-fat, Western diet administered to 1-year-old aMHCll^-/- Ldlr^-/- mice and myeloid-adipo-specific MHCII knockout mice (m-aMHCll [myeloid-adipocyte MHCII]^-/-) ingesting a Western high-fat diet, had no effect on disease progression.</p><p><strong>Conclusions: </strong>These results suggest that AT immunosuppressive T cells play a pivotal role in regulating both atherosclerosis development and liver fat accumulation in obesity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148787589","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":"SGLT2 Inhibitors Promote Diabetic Wound Healing Via AMPK/AKT/mTORC1-Regulated Endothelial Angiogenesis.","authors":"Furkan Bestepe, George F Ghanem, Caroline Kelly, Kamran Huseynli, Danielle V Richards, Rachel Barber, Annabelle Zamary, Parul Sahu, Payam Salehi, Gordon S Huggins, Basak Icli","doi":"10.1161/ATVBAHA.126.324596","DOIUrl":"10.1161/ATVBAHA.126.324596","url":null,"abstract":"<p><strong>Background: </strong>Approximately 25% of patients with type 2 diabetes are at risk of developing diabetic ulcers, which can progress to amputations. A key challenge in diabetic wound healing is impaired angiogenesis. Although SGLT2 (sodium-glucose transporter 2) inhibitors are known for their cardiovascular and renal benefits, their role in wound healing and angiogenesis, remains incompletely understood.</p><p><strong>Methods: </strong>We evaluated the effects of empagliflozin, dapagliflozin, and canagliflozin on wound healing in db/db mice by measuring wound closure, granulation tissue thickness, and perfusion. Angiogenesis and proliferation were assessed by CD31 and Ki67 immunostaining. Ex vivo studies used human skin organoids, sprouting assays from human microvessels and murine aortic explants. In vitro studies were performed in human umbilical vein endothelial cells (ECs).</p><p><strong>Results: </strong>Empagliflozin and dapagliflozin significantly improved wound healing, perfusion, angiogenesis, and cell proliferation while canagliflozin showed limited benefit. In human skin organoids and ECs, empagliflozin and dapagliflozin but not canagliflozin improved wound closure, angiogenesis, proliferation, and migration. Sprouting angiogenesis of human vascular explants and mice aorta showed significantly increased branching and junction formation in response to empagliflozin and dapagliflozin. All 3 SGLT2 inhibitors similarly suppressed inflammation and improved EC barrier function, while empagliflozin and dapagliflozin selectively increased tissue remodeling gene expression. Mechanistically, canagliflozin significantly increased AMPK (AMP-activated protein kinase) phosphorylation while decreasing AKT/mTORC1 (mechanistic target of rapamycin complex 1) activation compared with empagliflozin, dapagliflozin. AMPK inhibition with compound C, or dose reduction of canagliflozin, partially restored AKT/mTORC1 signaling and wound closure.</p><p><strong>Conclusions: </strong>These findings uncover distinct angiogenic effects among SGLT2 inhibitors. Empagliflozin and dapagliflozin promote EC-angiogenic functions through balanced AMPK/AKT/mTORC1 signaling, whereas canagliflozin impaired these processes via excessive AMPK activation and suppression of AKT/mTORC1 signaling. AMPK inhibition or dose reduction restored AKT/mTORC1 signaling and partially rescued wound healing, underscoring the importance of balanced AMPK/AKT/mTORC1 signaling for EC-angiogenic function in diabetic wounds.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324596"},"PeriodicalIF":8.8,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315396","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}