Tanwar VS, Malek V, Wang J
… +12 more, Luo Y, Malhi NK, Zhang H, Abdollahi M, Lanting L, Senapati P, Das S, Reddy MA, Zang C, Miller CL, Chen ZB, Natarajan R
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41641545
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BACKGROUND: Type 2 diabetes is associated with accelerated vascular complications such as hypertension and atherosclerosis. Phenotypic switching of vascular smooth muscle cells (SMCs), a major driver of these complicatio...BACKGROUND: Type 2 diabetes is associated with accelerated vascular complications such as hypertension and atherosclerosis. Phenotypic switching of vascular smooth muscle cells (SMCs), a major driver of these complications, is enhanced in diabetes. Despite adequate glycemic control, SMC dysfunction can persist due to metabolic memory of prior hyperglycemia. However, the mechanisms are unclear. Here, leveraging single-cell multiomics, we examined the effect of glucose normalization on transcriptomic and epigenomic changes associated with SMC phenotypic transition in type 2 diabetes mice. METHODS: Type 2 diabetes db/db mice were treated with the antidiabetic drug dapagliflozin (DAPA) or vehicle and nondiabetic control db/+ mice with vehicle for 6 weeks. Dissected aortas were subjected to single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin with sequencing, and spatial transcriptomics (Xenium) to determine single-cell changes in gene expression and chromatin accessibility. RESULTS: DAPA conferred effective glycemic control in db/db mice, with significant reductions in blood glucose and hemoglobinA1c. scRNA and single-cell assay for transposase-accessible chromatin with sequencing analysis of aortas identified SMC, fibroblasts, endothelial, and immune cells. SMCs were further clustered into 9 subtypes, including contractile and fibromyocyte-like cells. Interestingly, SMC contractile phenotype-associated pathways decreased in diabetes and remained decreased despite DAPA treatment. Fibrosis and inflammation-associated pathways in SMC and fibroblasts, and dysfunction markers in endothelial cells, increased in diabetes and were partly reversed by DAPA. Pseudotime trajectory analysis of SMC revealed increased activities of fibromyocyte-enriched TFs (transcription factors) during the contractile to fibromyocyte transition. Pairwise analysis for differentially accessible regions revealed diabetes-associated differentially accessible regions, enrichment of TF motifs, and related disease-associated biological processes. However, no differentially accessible regions were identified between db/db and db/dbDAPA groups. Spatial transcriptomics mapped aortic cell types within intact aortas and validated single-cell sequencing data. CONCLUSIONS: Type 2 diabetes induces gene expression and chromatin accessibility changes associated with profound SMC phenotypic switching. These changes are not efficiently reversed by a widely used antidiabetic drug, DAPA, underscoring the need for more effective therapies targeting hyperglycemic memory.
Vazquez-Padron RI, Yu J, Tabbara M
… +1 more, Martinez L
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41641544
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Achieving a mature arteriovenous fistula (AVF) for hemodialysis remains a significant challenge, even for the most experienced vascular surgeons. Despite decades of research, ≈40% of new AVFs require salvage intervention...Achieving a mature arteriovenous fistula (AVF) for hemodialysis remains a significant challenge, even for the most experienced vascular surgeons. Despite decades of research, ≈40% of new AVFs require salvage interventions or can never be used for dialysis. All clinical trials aimed at improving early AVF maturation have failed. This underscores the limitations of the existing biological model, which continues to frame stenosis through a reductionist lens centered on intimal hyperplasia, despite emerging evidence that this explanation is insufficient. This review seeks to redefine the biological framework of early AVF failure by adopting a human-centered perspective. In contrast to the prevailing paradigm, primarily built upon experimental data, our model is centered on human observational research and clinical trials. We then incorporate experimental data to provide mechanistic insights and contextualize or contrast the differences between human and animal biology. We unravel the biology of AVF maturation through 2 tightly connected phases: the acute biomechanical response, encompassing immediate structural and hemodynamic changes after AVF creation, and the subsequent vascular healing and remodeling processes that determine the long-term adaptation of the vein to supraphysiological circulation. By integrating these phases into a cohesive framework, this review advances a more comprehensive model of early AVF maturation failure, highlights therapeutic opportunities, and underscores that meaningful innovation in AVF biology remains both necessary and achievable.
Huchzermeier R, de Jong RJ, Rakateli L
… +12 more, Bonnin-Marquez A, Maas SL, Maassen-Pöttgens C, Abschlag K, Jin H, Geiselhöringer AL, Triantafyllidou V, Santovito D, Jankowski J, Biessen EAL, Ohnmacht C, van der Vorst EPC
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41608774
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BACKGROUND: Atherosclerotic cardiovascular disease, characterized by an imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The AhR (aryl hydrocarbon receptor) is a ligand...BACKGROUND: Atherosclerotic cardiovascular disease, characterized by an imbalanced lipid metabolism and a dysregulated immune response, is a major cause of death worldwide. The AhR (aryl hydrocarbon receptor) is a ligand-activated transcription factor that is highly expressed in the liver and primarily known for its role in detoxification. However, recent studies suggest that the AhR also plays a key role in immune regulation, indicating that this receptor can influence the development of atherosclerosis. METHODS: and mice were fed a western-type diet for 12 weeks to induce atherosclerosis. Aortic roots were analyzed for size and composition of atherosclerotic plaques. Plasma samples were characterized for inflammation and lipid levels. Liver samples were analyzed for cytokines and lipid accumulation and subjected to RNA sequencing and kinomics. A PheWAS (Phenome-Wide Association Study) was performed to identify associations of genetic variants with atherosclerotic cardiovascular disease and lipid phenotypes in humans. RESULTS: The number of circulating leukocytes was increased in mice compared with controls. Surprisingly, however, mice lacking showed significantly smaller plaques than mice, which coincided with strongly reduced plasma cholesterol and triglyceride levels. The liver lipid levels showed a similar effect, indicating a key role of the AhR in lipid metabolism. RNA sequencing of the liver revealed that lipid metabolism pathways were particularly impacted in mice. Furthermore, through kinomics, we identified signaling pathways affected by the absence of . PheWAS analysis revealed significant associations between the variant rs4410790 and lipid traits, including plasma triglycerides, LDL (low-density lipoprotein), and total cholesterol. CONCLUSIONS: Our study demonstrates a remarkable role for AhR in the pathogenesis of atherosclerosis, interfering with both lipid metabolism and inflammatory pathways. Although the underlying mechanisms remain unclear, these results demonstrate a novel and crucial role for AhR in atherosclerotic cardiovascular disease.
He M, Sun Y, Tang C
… +8 more, Huang F, Zhu Z, Lee S, Velazquez-Miranda E, Ahn W, Malhotra R, Chong Z, Chen Y
Arterioscler Thromb Vasc Biol
· 2026 Apr · PMID 41608773
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BACKGROUND: Vascular calcification is a major contributor to cardiovascular morbidity and mortality in diabetes and is driven in part by osteogenic reprogramming of vascular smooth muscle cells (SMCs). Diabetes is also a...BACKGROUND: Vascular calcification is a major contributor to cardiovascular morbidity and mortality in diabetes and is driven in part by osteogenic reprogramming of vascular smooth muscle cells (SMCs). Diabetes is also associated with circadian rhythm disruption; however, how circadian regulators contribute to vascular calcification remains poorly understood. We investigated the role of the core circadian protein Bmal1 (basic helix-loop-helix ARNT-like protein 1) in diabetes-associated vascular calcification. METHODS: Bmal1 expression was examined in diabetic mouse aortas, human diabetic arterial tissues, and vascular SMCs exposed to high glucose. SMC-specific Bmal1 knockout mice were generated and subjected to low-dose streptozotocin-induced diabetes. Vascular calcification and stiffness were assessed by calcium staining and quantification, and pulse wave velocity. RNA sequencing, chromatin immunoprecipitation, luciferase reporter assay, and clustered regularly interspaced short palindromic repeats-clustered regularly interspaced short palindromic repeat-associated 9-mediated genome editing were used to define Bmal1-regulated molecular mechanisms. RESULTS: Bmal1, but not other circadian regulators, was selectively upregulated in diabetic arteries and vascular SMCs under hyperglycemic conditions. SMC-specific deletion of Bmal1 markedly attenuated diabetes-induced vascular calcification, reduced aortic stiffness, and suppressed osteogenic gene expression in vivo and in vitro. RNA-sequencing analysis revealed enrichment of Bmal1-dependent genes involved in osteogenic differentiation and extracellular matrix organization. Mechanistically, Bmal1 directly binds to an E-box motif in the Runx2 (Runt-related transcription factor 2) promoter, enhancing Runx2 transcription independently of canonical circadian pathways. Disruption of Bmal1 binding to the Runx2 promoter abolished Bmal1-induced Runx2 expression. CONCLUSIONS: Our findings identify Bmal1 as a key mediator of diabetes-induced vascular calcification through direct transcriptional regulation of Runx2 via a noncanonical circadian mechanism. These results reveal a previously unrecognized pathogenic role for Bmal1 in vascular disease and suggest that targeting dysregulated circadian factors may represent a novel therapeutic strategy for preventing vascular calcification in diabetes.
Anderson BJ, Moss CE, Lee DD
… +10 more, Czepielewski RS, Helmink BA, Onufer EJ, Davis DL, Strickland MR, Kurashima K, Jain AK, Coon JJ, Randolph GJ, Overmyer KA
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41568461
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BACKGROUND: The venous and lymphatic outflows from organs may contain molecular signatures related to tissue function, but deep biomolecular analyses that compare outflow composition are lacking. Here, using blood and ly...BACKGROUND: The venous and lymphatic outflows from organs may contain molecular signatures related to tissue function, but deep biomolecular analyses that compare outflow composition are lacking. Here, using blood and lymph samples from a piglet model system and mass spectrometry analysis, we compare protein and lipid cargo from 9 venous and 3 lymph depots centered on intestinal outflow. METHODS: We obtained venous blood and plasma from piglets using new methods for dissection and sample collection. We applied mass spectrometry-based proteomics and lipidomics, using both a low-volume method and an additional proteomics sample preparation method, the Seer Proteograph XT high coverage method for the proteomics. RESULTS: We detected 622 proteins and 1315 lipids across lymph and plasma. With the additional Seer proteomics method, we detected a further 7771 proteins across a subset of samples. We observed both expected and novel enrichments of proteins, including CCL21 (C-C motif chemokine ligand 21) and IGFBP (insulin-like growth factor-binding protein) 7 as proteins strongly enriched in lymph. When comparing lymph depots, we found that thoracic duct lymph is distinct from lymph draining the proximal and distal small intestine, especially in their lipidomic profiles, possibly reflecting differences in dietary lipid uptake. By performing integrative multiomics of proteomics and lipidomics, we show that apoproteins, such as the related apoA1 (apoprotein A1) and apoA2 (apoprotein A2) proteins, correlate with different lipid profiles and may associate with distinct functions across the plasma depots. CONCLUSIONS: These data identify molecules and biomarkers selectively enriched in adjacent lymph and venous drainage depots from the gastrointestinal tract. The analyses and figures present in this work are expanded upon in an interactive companion Web application at gutveinlymphomics.com, facilitating access to our integrated multiomics and advancing understanding of biomolecular trends across the intestinal tract.
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41568460
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Sleep behavior has emerged as an important determinant of cardiometabolic health. However, to date, much attention has focused on sleep duration with accumulating evidence resulting in leading medical organizations to in...Sleep behavior has emerged as an important determinant of cardiometabolic health. However, to date, much attention has focused on sleep duration with accumulating evidence resulting in leading medical organizations to include adequate sleep duration in their recommendations for disease risk prevention and health promotion. However, sleep is a multidimensional construct that extends beyond sleep duration and includes factors related to the variability of duration but also to the regularity in its timing across days. These concepts, termed sleep duration variability (day-to-day differences in sleep amounts) and sleep timing regularity (day-to-day differences in sleep timing), can influence the circadian system and have independent health effects beyond sleep duration per se. Here, we assess the literature evaluating the association of fluctuations in sleep behaviors over time and cardiometabolic risk factors and their potential implications for chronic disease development. We conclude that large-scale population-based studies support an adverse relation between fluctuations in sleep behaviors and cardiovascular disease risk markers, but caution that causality should be evaluated in clinical intervention studies.
Perivascular adipose tissue (PVAT) has been widely studied over the past 2 decades for its anticontractile function, morphology, and adipokine secretion. However, most data were obtained from male sex, with few studies o...Perivascular adipose tissue (PVAT) has been widely studied over the past 2 decades for its anticontractile function, morphology, and adipokine secretion. However, most data were obtained from male sex, with few studies on female PVAT. Indeed, the PVAT secretome, adipocyte phenotype, progenitor cells, and responses to cardiovascular risk factors exhibit sex differences and may be modulated by sex hormones. Here, we compiled data evaluating PVAT based on sex differences or focused on the female sex. Sex comparisons in PVAT function and morphology under physiological conditions and in pathological states such as dyslipidemia, atherosclerosis, obesity, heart failure, and hypertension have been briefly reviewed.
Hur WS, Patel YN, Abrahams SR
… +10 more, Wei Z, Hanes HE, Jameson AT, Negrón OA, Pedersen NB, Giacomazzo MSY, Bladbjerg EM, Wolberg AS, Luyendyk JP, Flick MJ
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41568458
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BACKGROUND: Obesity predisposes individuals to multiple pathologies, including metabolic dysfunction-associated steatotic liver disease and diabetes. Although it is known that accumulation of proinflammatory macrophages...BACKGROUND: Obesity predisposes individuals to multiple pathologies, including metabolic dysfunction-associated steatotic liver disease and diabetes. Although it is known that accumulation of proinflammatory macrophages within adipose tissues drives adiposity and provokes obesity-linked sequelae, the molecular mechanisms that provoke macrophage dysfunction in obesity remain elusive. Macrophages express high levels of uPA (urokinase plasminogen activator), and uPA has been implicated in leukocyte migration. METHODS: Human adipose tissues from patients receiving bariatric surgery were collected and analyzed for uPA protein levels. To determine the impact of uPA in adipose tissue and subsequent high-fat diet (HFD)-induced weight gain and metabolic diseases, a novel mouse model with a conditional knockout of uPA () was generated. , (global uPA deficiency), and (conditional uPA deficiency in macrophages) mice were fed low-fat diet or HFD for up to 20 weeks. RESULTS: Protein levels of visceral adipose tissue uPA positively correlated with body mass index in patients with obesity, and uPA levels decreased in adipose tissue 2 years after bariatric surgery. The expression and activity of uPA also increased in the adipose tissue of HFD-fed control mice. mice displayed reduced weight gain and metabolic sequelae through 14 weeks on a HFD compared with mice, but not with prolonged HFD feeding. Interestingly, mice developed HFD-induced metabolic pathologies equivalently to mice. CONCLUSIONS: Our findings suggest that global uPA deletion, but not selective deletion of uPA in LysM+ myeloid cells, attenuates the development of early-stage HFD-driven obesity and pathologies consistent with metabolic syndrome.
Despite major advances in acute reperfusion therapies, patients surviving ischemic stroke or myocardial infarction remain at high risk for long-term cardiovascular and metabolic comorbidities. Emerging evidence identifie...Despite major advances in acute reperfusion therapies, patients surviving ischemic stroke or myocardial infarction remain at high risk for long-term cardiovascular and metabolic comorbidities. Emerging evidence identifies trained immunity, the long-lasting reprogramming of innate immune progenitors, as a central driver of this interorgan communication. Sterile insults such as stroke or myocardial infarction imprint persistent inflammatory memory via long-lasting reprogramming of bone marrow hematopoietic progenitors, biasing myelopoiesis and generating proinflammatory monocytes that target distant organs. This central trained immunity explains how a single ischemic event can precipitate cardiac dysfunction, accelerate atherosclerosis, or exacerbate metabolic disease, thereby contributing to multimorbidity in vascular patients. Understanding these systemic immune circuits provides a conceptual framework for developing interventions that interrupt maladaptive inflammatory memory. Finally, we discuss emerging therapeutic strategies to prevent maladaptive innate immune memory and mitigate chronic vascular inflammation and multimorbidity.
Yamada Y, Satoh T, Yaoita N
… +18 more, Yamada K, Chiba N, Komaru K, Nochioka K, Yamamoto S, Sato H, Kikuchi N, Nakata T, Sunamura S, Inoue T, Hayashi H, Suzuki H, Tatebe S, Takahama H, Oishi H, Miyata S, Okada Y, Yasuda S
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41568456
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BACKGROUND: Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involv...BACKGROUND: Pulmonary hypertension (PH) due to left heart disease (group 2 PH) is associated with a worse prognosis than isolated heart failure. Both pulmonary arterial hypertension (group 1 PH) and group 2 PH are involved in pulmonary artery (PA) remodeling, which is potentially driven by shared molecular mechanisms. The aim of this study was to investigate the underlying processes contributing to PA remodeling in group 2 PH. METHODS: To mimic the response to a left-sided pressure load, pulmonary arterial smooth muscle cells (PASMCs) were subjected to mechanical stretch. RNA sequencing of PAs from patients with group 2 PH was performed using the Gene Expression Omnibus database. Mice with transverse aortic constriction and spontaneously hypertensive rats were used as group 2 PH models, and they were treated with adeno-associated virus via intratracheal instillation. RESULTS: RNA sequencing of PASMCs after the stretch stress identified 1585 genes specifically upregulated in PASMCs from patients with group 1 PH. Further PA and plasma analyses from patients with group 2 PH, integrated with group 1 PH findings, identified enhancement of TGF-β (transforming growth factor-beta) signaling by the INHBA (inhibin subunit beta A) as a key feature. Metabolomics revealed that stretch-induced mitochondrial dysfunction in PASMCs caused lactic acidosis via enhancement of PDK1 (pyruvate dehydrogenase kinase 1) and c-MYC, leading to increased INHBA expression. Mice with transverse aortic constriction exhibited increased INHBA expression, decreased PDH (pyruvate dehydrogenase) expression, and acidic alterations in PAs. Targeted silencing of INHBA or PDK1 using adeno-associated virus in mice with transverse aortic constriction attenuated PA remodeling, improved right ventricular function, and reduced PH. CONCLUSIONS: Integrated RNA sequencing and metabolomics with stretched PASMCs and animal models identified mitochondrial dysfunction and subsequent acidic alterations as stimulators of increased INHBA expression and TGF-β signaling. These mechanisms contributed to PA remodeling in group 2 PH and provided potential therapeutic strategies.
Yuan L, Han J, Cheng S
… +10 more, Rosendaal FR, Mook-Kanamori DO, Jukema JW, Vink H, van den Berg BM, Rabelink TJ, van Hylckama Vlieg A, Tietge UJF, Willems van Dijk K, Li-Gao R
Arterioscler Thromb Vasc Biol
· 2026 Feb · PMID 41564160
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BACKGROUND: Recent evidence points to connections between HDLs (high-density lipoproteins), the coagulation system, and venous thromboembolism occurrence. However, uncertainty remains regarding the impact of specific HDL...BACKGROUND: Recent evidence points to connections between HDLs (high-density lipoproteins), the coagulation system, and venous thromboembolism occurrence. However, uncertainty remains regarding the impact of specific HDL characteristics on the coagulation system. This study investigated associations between HDL characteristics and hemostatic parameters in a large middle-aged Dutch population. METHODS: Using baseline measurements from 6245 participants in NEO study (the Netherlands Epidemiology of Obesity), we performed adjusted linear regression analyses to estimate associations between 34 parameters of XLHDL (very large HDL), LHDL (large HDL), MHDL (medium HDL), and SHDL (small HDL) particles, as well as ApoA1 (apolipoprotein A1), quantified using a high-throughput H-nuclear magnetic resonance metabolomics platform, and coagulation parameters. These included coagulation factor (F) VIII, FIX, FXI, and fibrinogen, along with 5 parameters of the thrombin generation potential. In addition, the associations between HDL characteristics and parameters of platelet activation and endothelial glycocalyx health were tested in a subpopulation. RESULTS: Our findings revealed a particle size-dependent association between HDL parameters and coagulation parameters. Particularly, per 1-SD increase in the levels of components within XLHDL (very large HDL), we observed lower levels in FIX and FXI activities, endogenous thrombin potential, and peak height (median β [interquartile range], FIX: 3.26% [-3.50% to -3.18%]; FXI: -0.96% [-1.21% to -0.89%]; endogenous thrombin potential: -22.11 [-27.07 to -21.47] nmol/L·min; and peak height: -2.28 [-2.70 to -2.19] nmol/L), indicating an antithrombotic effect. In contrast, per 1-SD increase in the levels of components within MHDL and SHDL, we observed an increase in endogenous thrombin potential, peak height, and activities of FVIII, FIX, and FXI, indicating a prothrombotic effect. HDL characteristics were not associated with platelet activation parameters or with glycocalyx-related parameters. CONCLUSIONS: Our study provides evidence for a size-dependent relationship between HDL components and coagulation parameters. These findings contribute to a better understanding of the potential role of HDL in the pathogenesis of venous thromboembolism.
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41537264
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Peripheral artery disease commonly refers to diffuse atherothrombotic disease of the arteries supplying the legs. Peripheral artery disease has been relatively understudied and has not been subject to the same intensive...Peripheral artery disease commonly refers to diffuse atherothrombotic disease of the arteries supplying the legs. Peripheral artery disease has been relatively understudied and has not been subject to the same intensive scrutiny and research that characterizes coronary artery disease. Moreover, the diagnosis of peripheral artery disease can be complicated by the presence of arterial calcification. Here, we provide a brief report on the current understanding of peripheral vascular calcification to include the following sections: basic mechanisms, anatomic distribution of arterial calcification, manifestations, risk factors, measurement of peripheral calcification, nonsurgical treatments, and surgical interventions.
Reventun P, Toledano-Sanz P, Delgado-Marin M
… +13 more, Viskadourou M, Foster DB, de Vries PS, Sabater-Lleal M, Alcharani N, Gonzalez-Cucharero C, Osburn WO, Morrison AC, Wolberg AS, Smith NL, Arvanitis M, Cohorts for Heart and Aging in Genomic Epidemiology Hemostasis Working Group, Lowenstein CJ
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41537263
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BACKGROUND: Abnormal levels of VWF (von Willebrand Factor) are a risk factor for venous thromboembolism (VTE) and bleeding. Genome-wide association studies for VWF have identified novel candidate genes that may regulate...BACKGROUND: Abnormal levels of VWF (von Willebrand Factor) are a risk factor for venous thromboembolism (VTE) and bleeding. Genome-wide association studies for VWF have identified novel candidate genes that may regulate VWF levels in humans, including (RAS [rat sarcoma]-associated protein RAB5C). We hypothesized that RAB5C regulates VWF release from endothelial cells. METHODS: We studied the effect of RAB5C on vesicle trafficking in human endothelial cells. We performed CRISPR (clustered regularly interspaced short palindromic repeats) interference targeting 2 genetic variants linked to altered VWF levels and evaluated RAB5C expression by reverse transcription-quantitative polymerase chain reaction. We silenced RAB5C or overexpressed RAB5C wild-type, constitutive active or dominant negative; and then, we measured VWF exocytosis from human umbilical vein endothelial cells to the media by ELISA. We performed proximity labeling and mass spectrometry to identify intracellular signaling pathways mediating the effects of RAB5C on VWF exocytosis. RESULTS: We found that 2 genetic variants (rs9915255 and rs9912088 identified by genome-wide association studies for VWF levels) regulate expression in stem cell-derived endothelial cells. We next silenced or overexpressed in endothelial cells to assess its effect on VWF release. silencing decreased VWF release after histamine stimulation, whereas overexpression of RAB5C or constitutively active RAB5C increased endothelial VWF release. To explore the intracellular signaling pathway mediating the effects of RAB5C on VWF exocytosis, we performed proximity labeling and mass spectrometry. We identified 147 proteins proximal to RAB5C, many of which are involved in vesicle trafficking. From this screen, we identified SNAP29 (synaptosome-associated protein 29), a SNARE (soluble NSF [N-ethylmaleimide-sensitive factor] attachment receptor)-associated protein that plays a crucial role in vesicle fusion, as a key RAB5C interactor regulating VWF exocytosis. CONCLUSIONS: Taken together, our data demonstrate that RAB5C regulates VWF release in part through SNAP29 control of vesicle trafficking in endothelial cells. These findings validate genetic epidemiology data linking RAB5C to VWF levels in humans and provide new insights into the molecular mechanisms regulating VWF exocytosis.
Perivascular adipose tissue (PVAT) is a metabolically active tissue that influences vascular function through paracrine signaling of adipokines. Pathologically altered PVAT is associated with proinflammatory, pro-oxidati...Perivascular adipose tissue (PVAT) is a metabolically active tissue that influences vascular function through paracrine signaling of adipokines. Pathologically altered PVAT is associated with proinflammatory, pro-oxidative, and proatherogenic signaling in coronary vessels, and consequently contributes to the pathophysiological mechanisms underlying atherosclerosis. Bidirectional cross talk from inflamed vasculature can also induce phenotypic changes in the PVAT that can be detected noninvasively with cross-sectional imaging. Imaging modalities like computed tomography are readily available in clinical settings, and PVAT characterization with Fat Attenuation Index has emerged as a valuable prognostic tool that quantifies coronary inflammation. This article reviews the imaging, quantification, and novel radiotranscriptomic analysis of PVAT. We also describe how these could integrate into artificial intelligence-enabled risk-prediction models for personalizing medical therapy guided by an individual's inflammatory risk, and how this approach already changes clinical management in healthcare systems where it has been adopted.
Suzuki N, Suzuki A, Tamura S
… +13 more, Tokumaru S, Notoh H, Takagi A, Suzuki S, Isotani A, Suzuki N, Okamoto S, Kanematsu T, Ikawa M, Hayakawa F, Kiyoi H, Kojima T, Matsushita T
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41503699
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BACKGROUND: Antithrombin resistance (ATR) is a congenital thrombotic predisposition caused by abnormal prothrombin, FII (Factor II). Abnormal FII with ATR characteristics, when converted to thrombin, FIIa (Factor IIa), s...BACKGROUND: Antithrombin resistance (ATR) is a congenital thrombotic predisposition caused by abnormal prothrombin, FII (Factor II). Abnormal FII with ATR characteristics, when converted to thrombin, FIIa (Factor IIa), shows a reduced affinity of binding to AT (antithrombin), resulting in reduced anti-FIIa and a thrombotic tendency. Data on the efficacy of anticoagulants in ATR are currently insufficient. METHODS: Mouse models of ATR were generated to investigate the efficacy of anticoagulants. Because FII R596L, which causes ATR in humans, was considered to correspond to R593L in mice based on gene sequence analysis, knock-in mice that systemically express FII R593L were generated. First, the nature of ATR was confirmed by blood coagulation analysis. We then evaluated thrombotic tendency at the individual level using an inferior vena cava stenosis model, and evaluated the antithrombotic effects of unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, and direct oral anticoagulants. RESULTS: In coagulation studies, R593L Homo and Hetero mice (R593L Homo and Hetero, respectively) exhibited lower FII antigen levels and lower FIIa generation potential than wild-type mice, but residual FIIa activity after addition of AT confirmed the presence of ATR properties. In the inferior vena cava stenosis model, significantly higher thrombus formation was maintained in R593L Homo and Hetero compared with wild-type, even 96 hours after inferior vena cava stenosis. In anticoagulant administration experiments, anticoagulants with anti-FIIa effects appeared more effective against FII R593L. CONCLUSIONS: Knock-in of FII R593L produced ATR model mice, which showed a strong thrombotic tendency. Evaluation of antithrombotic therapies showed that anticoagulants with anti-FIIa effects were highly effective.
Arterioscler Thromb Vasc Biol
· 2026 Mar · PMID 41503698
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Enhancers are regulatory DNA sequences that increase the transcription of a target gene when bound by transcription factors. Decades of research endeavors have shed light on the crucial roles of enhancers in cardiovascul...Enhancers are regulatory DNA sequences that increase the transcription of a target gene when bound by transcription factors. Decades of research endeavors have shed light on the crucial roles of enhancers in cardiovascular development and disease. Besides working as cis-regulatory elements, enhancers also play critical roles in transactivating mechanisms such as enhancer RNA transcription and transcriptional condensates. Technological advances, such as single-cell multiomics, CRISPR (clustered regularly interspaced short palindromic repeats)-based enhancer perturbation screens, and machine learning technologies, provide us with unprecedented opportunities to gain novel insights into the dynamic function of cardiovascular enhancers. In this brief review, we discuss cutting-edge techniques that are being or can be leveraged to fill knowledge gaps in studying cardiovascular enhancers. Like gene expression, enhancers display functional dynamics in concordance with specific cellular stress. We summarize the findings of inducible enhancer functions in the cardiovascular system. We also discuss several recent studies that are advancing our understanding of cardiovascular enhancer functions and are potentially paradigm-shifting. These insights have great potential to inform novel therapeutic strategies targeting enhancer-mediated gene dysregulation in cardiovascular disease.
Arterial dilation can lead to aneurysm formation, most commonly affecting the aorta and intracranial arteries. Platelets are now recognized as key mediators of vascular inflammation and remodeling, contributing to the in...Arterial dilation can lead to aneurysm formation, most commonly affecting the aorta and intracranial arteries. Platelets are now recognized as key mediators of vascular inflammation and remodeling, contributing to the initiation and progression of several vascular diseases. While the role of platelets in abdominal aortic aneurysm formation has gained considerable attention and is under active investigation, their contribution to intracranial aneurysm pathophysiology remains poorly understood. In this review, we summarize current mechanistic and preclinical evidence on the development and rupture of intracranial aneurysms. We discuss how platelet interactions with leukocytes, vascular cells, and their procoagulant role may influence inflammatory and tissue damage within the intracranial aneurysm, highlighting gaps in knowledge that could reveal new mechanisms.