Arteriosclerosis, Thrombosis, And Vascular Biology[JOURNAL]
Sun
200 papers
Macrophages and the Survival of Cardiomyocytes After Myocardial Infarction.
Zhang M, Tao G
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42206365 · Full text
Myocardial infarction (MI) causes a severe burden to public health worldwide. After MI, stressed cardiomyocytes undergo necrosis and regulated cell death. Dynamic cell cascades ensue to limit tissue injury and promote he...
Myocardial infarction (MI) causes a severe burden to public health worldwide. After MI, stressed cardiomyocytes undergo necrosis and regulated cell death. Dynamic cell cascades ensue to limit tissue injury and promote healing. MI and subsequent ischemic injury trigger the influx of innate immune cells. Macrophages, among the first responders of MI, are known mostly to coordinate the scavenging of dead cardiomyocytes. However, rather than occurring as a homogenous population, macrophages have diverse ontogenies and pathological functions, exhibiting contradictory roles in the survival and death of cardiomyocytes. This review focused on macrophages and discussed their diverse dynamics and functional patterns after MI. We shared the insight into the roles of macrophages in cardiomyocyte survival and regulated cell death. We explored the use of single-cell technology to discriminate specific macrophage clusters that can provide clues for the precise targeting of cardiomyocyte survival after MI.
Spatial and Single-Cell Mapping Reveals Valvular Interstitial Cell and Macrophage Sex Differences in Calcific Aortic Valve Disease.
Baddour T, Ninh VK, Gorashi RM … +3 more , Peña R, King KR, Aguado BA
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42206364 · Full text
BACKGROUND: Sex differences in calcific aortic valve disease (CAVD) progressing to aortic valve stenosis have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent fibrocalcification...
BACKGROUND: Sex differences in calcific aortic valve disease (CAVD) progressing to aortic valve stenosis have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent fibrocalcification in aortic valve tissue remain poorly understood. METHODS: Human aortic valve tissues were analyzed via histological techniques and scanning electron microscopy to visualize and quantify sites of calcification. Single-cell and spatial transcriptomics were used to investigate mechanisms that drive sex-dependent spatial organization of valvular interstitial cell (VIC) and macrophage gene expression near calcification sites in human male and female aortic valve tissues. RNA in situ hybridization was used to validate sex-dependent gene expression near sites of calcification, and cell communication analyses were performed using bioinformatics tools to determine sex-dependent pathological cell-cell interactions. RESULTS: Histological analyses of aortic valve tissues from healthy patients and patients with CAVD reveal increased valve calcification area in CAVD male aortic valves relative to female valves. Single-cell sequencing analysis of heterogeneous VIC populations reveals male-biased gene expression of the AP-1 (activator protein 1) transcription factor complex and female-biased ECM (extracellular matrix) remodeling genes. Spatial transcriptomics analyses of VIC populations near histologically defined calcification sites revealed male-dependent localization of or cartilage oligomeric matrix protein, as opposed to nonlocalized expression in female VICs. Female CAVD tissues with increased fibrotic density had elevated expression of , encoding PAI-1 (plasminogen activator inhibitor-1), relative to male tissues. Female CAVD tissues also exhibited increased macrophage count heterogeneity relative to male tissues. Candidate ligand-receptor interactions, including osteopontin () interacting with , which encodes a cell-surface glycoprotein, were identified as contributors to inflammation-mediated CAVD. CONCLUSIONS: Our results reveal sex differences in VIC and macrophage heterogeneity and functions near sites of calcification in aortic valve tissue. Our results highlight the importance of sex-based transcriptomics analyses to understand the cellular phenotypes responsible for causing sex differences in aortic valve fibrocalcification.
Clonal Hematopoiesis Does Not Promote Atherosclerosis in Murine Models.
De Jeronimo Diaz C, Liao H, Hardaway B … +14 more , Li L, Gan AL, Liu M, Kim A, Qian G, Abramowicz S, Lam E, Tseng ZH, Devine WP, Tall AR, Yu Z, Miller PG, Ebert BL, Fidler TP
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42165150 · Full text
BACKGROUND: Clonal hematopoiesis (CH) is an age-associated condition common in the elderly that arises when hematopoietic stem cells acquire somatic mutations in an assortment of genes, most commonly , , , , and CH is a...
BACKGROUND: Clonal hematopoiesis (CH) is an age-associated condition common in the elderly that arises when hematopoietic stem cells acquire somatic mutations in an assortment of genes, most commonly , , , , and CH is associated with increased coronary artery disease and all-cause mortality. Epidemiological studies have revealed that different CH driver mutations are associated with unique outcomes. CH is more prevalent in patients following radiation and cytotoxic therapy. CH has been strongly associated with coronary artery disease, peripheral artery disease, and all-cause mortality. However, it is unclear if this relationship is causative. METHODS: We tested the ability of mutations to promote atherosclerosis in mice. To model CH, we transplanted a mixture of 20% bone marrow from mice expressing * truncation mutation under the control of an and 80% wild-type bone marrow into recipient mice and subjected them to atherosclerosis studies. In parallel, -driven * mutations were introduced into mice for atherosclerosis studies. To examine the interaction between DNA damage and , we transplanted bone marrow with mutations restricted to monocyte/macrophage or pan-hematopoietic expression of * into mice. Cisplatin was administered after the establishment of atherosclerosis, and lesion burden and inflammasome activation were quantified. RESULTS: We found that in vitro mutant macrophages have increased AIM2 (absent in melanoma 2) inflammasome activation and increased inflammasome activation in response to cisplatin. However, in vivo, we found no evidence of elevated inflammasome activation in plaques. Across both and knockout models, hematopoietic mutations did not promote atherosclerosis. Furthermore, mutations did not exacerbate atherosclerosis following administration of cisplatin. CONCLUSIONS: These findings indicate that in murine models, mutations are not sufficient to promote atherosclerosis, suggesting that the epidemiological association between CH and coronary artery disease may not be due to changes in plaque development.
Interplay of Multipathway Dyslipidemia, Inflammation, and Cholesterol-Lowering Medication in Modifying Abdominal Aortic Aneurysm Risk.
Wu Y, Chen D, Zhang Y … +9 more , Ye Z, Yang S, Gan X, Huang Y, Zhang Y, Cai X, Liang X, Zhang Y, Qin X
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42165149 · Publisher ↗
BACKGROUND: Abdominal aortic aneurysm (AAA) carries high rupture mortality, yet medical therapies remain limited. While dyslipidemia and inflammation are implicated in AAA pathogenesis, the individual and joint roles of...
BACKGROUND: Abdominal aortic aneurysm (AAA) carries high rupture mortality, yet medical therapies remain limited. While dyslipidemia and inflammation are implicated in AAA pathogenesis, the individual and joint roles of key lipid fractions, LDL-C (low-density lipoprotein-cholesterol), Lp(a) (lipoprotein[a]), and remnant cholesterol (RC), with systemic inflammation, are not fully established, particularly in the context of widespread cholesterol-lowering medication use. METHODS: We performed a prospective analysis of 338 758 UK Biobank participants free of AAA at baseline. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for associations between biomarkers and incident AAA. RESULTS: Over a median follow-up of 13.65 years, 1694 incident AAA cases occurred. Among participants not taking cholesterol-lowering medication, concurrent elevations of LDL-C, Lp(a), and RC (>75th percentile) conferred the highest risk (adjusted HR, 2.53 [95% CI, 1.97-3.24]). Coexisting elevated Hs-CRP (high-sensitivity C-reactive protein) with this triple-lipid elevation further increased the risk (adjusted HR, 4.19 [95% CI, 2.97-5.91]). Among cholesterol-lowering medication users, significant associations persisted for LDL-C (adjusted HR, 1.19 [95% CI, 1.09-1.29]) and RC (adjusted HR, 1.22 [95% CI, 1.14-1.31]) but not for Lp(a) (adjusted HR, 1.03 [95% CI, 0.97-1.10]). In this group, the combination of elevated LDL-C, RC, and Hs-CRP was associated with the greatest risk (adjusted HR, 2.46 [95% CI, 1.86-3.26]). CONCLUSIONS: Combined elevations of multiple lipid fractions and systemic inflammation were associated with a substantially increased risk of AAA. Cholesterol-lowering medication was associated with an attenuated risk relationship for LDL-C and Lp(a) but not for RC or Hs-CRP. Comprehensive risk assessment integrating a full lipid profile and Hs-CRP can improve identification of high-risk phenotypes for targeted AAA prevention.
Mouse, Pig, and Human Atherosclerotic Lesions Have Common and Distinct Mesenchymal Cell Populations.
Sharysh D, Nogales P, Morales-Cano D … +5 more , Markov A, Izquierdo-Serrano R, Carramolino L, Albarrán-Juárez J, Bentzon JF
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42165148 · Publisher ↗
BACKGROUND: Smooth muscle cell (SMC) proliferation and phenotypic transitioning drive the accumulation of a heterogeneous population of mesenchymal cells in advanced atherosclerosis, with additional contributions reporte...
BACKGROUND: Smooth muscle cell (SMC) proliferation and phenotypic transitioning drive the accumulation of a heterogeneous population of mesenchymal cells in advanced atherosclerosis, with additional contributions reported from endothelial-mesenchymal transitioning and invading adventitial cells. Animal models enable investigations of their recruitment and function, but it remains unclear to what extent mesenchymal cell populations in these models recapitulate human disease. Here, we compared mesenchymal cell diversity in typical mouse and pig experimental lesions with clinically relevant human plaques. METHODS: Single-cell RNA sequencing data sets from human carotid and coronary arteries, pig aorta and coronary arteries, and mouse brachiocephalic arteries were integrated using multiple parallel integration algorithms and gene homology-matching strategies. Cross-species comparisons were based on consensus among multiple methods, and cell populations of interest were localized in plaques using immunofluorescence and in situ hybridization. RESULTS: The cross-species analysis revealed a conserved mesenchymal cell continuum, spanning contractile smooth muscle cells to extracellular matrix-producing fibroblast-like cells, that was stable across species and vascular beds. Yet several other populations differed between human and experimental lesions. Subpopulations of smooth muscle cells marked by and expression were unique to human carotid and coronary plaques, respectively. Mesenchymal cell states with strong pro-angiogenic and inflammation-associated gene signatures were enriched in pig compared with human coronary lesions, with the proangiogenic phenotype associated with early stages of necrotic core development. Pericytes were solely present in pig and human plaques, while chondrocyte-like cells were abundant in mouse lesions, uncommon in pigs, and absent in the analyzed human lesions. CONCLUSIONS: Human and experimental atherosclerosis share core mesenchymal cell phenotypes, but several distinct subtypes differ in presence or abundance. Recognizing these differences-whether reflecting species-specific regulation or variations in lesion site, stage, or disease activity-can inform the use of animal models to investigate smooth muscle cell-derived and other types of mesenchymal cells in atherosclerosis.
Single-Cell Spatial Transcriptomics Reveals Sex-Specific Differences Driving Carotid Atherosclerotic Plaque Instability.
Byun JH, Papacostas Quintanilla H, Gasbarrino K … +7 more , Gianopoulos I, Harutyunyan AS, Oikonomopoulos S, Veinot JP, Zheng H, Ragoussis J, Daskalopoulou SS
Arterioscler Thromb Vasc Biol · 2026 May · PMID 42165147 · Publisher ↗
BACKGROUND: Ischemic stroke remains a leading contributor to cardiovascular disease, and unstable atherosclerotic plaques in the carotid arteries are an important contributor to its pathogenesis. Notably, sex differences...
BACKGROUND: Ischemic stroke remains a leading contributor to cardiovascular disease, and unstable atherosclerotic plaques in the carotid arteries are an important contributor to its pathogenesis. Notably, sex differences exist in plaque composition and morphology; whereas males are more likely to develop unstable plaques, females present with worse outcomes poststroke. As such, this study aims to elucidate sex-specific cellular and molecular mechanisms driving carotid plaque instability. METHODS: We performed single-cell RNA sequencing on carotid endarterectomy specimens from male and female patients with stable or unstable plaques, profiling over 64 000 cells. To spatially contextualize these findings, we integrated single-cell RNA sequencing data with CosMx high-plex spatial transcriptomics using the human discovery 6k RNA panel to map gene expression and cell type localization within key histological regions defining instability. RESULTS: Single-cell RNA sequencing revealed that vascular smooth muscle cells (VSMCs), T lymphocytes, and macrophages comprised ≈88% of plaque-resident cells, with distinct sex-specific differences in relation to instability. In males, unstable plaques showed depletion of contractile VSMCs, and abundance of inflammatory synthetic and macrophage-like VSMCs, alongside increased inflammatory macrophages and activated naive T lymphocytes. In contrast, female unstable plaques retained relatively more contractile VSMCs but exhibited greater expansion of cytotoxic T lymphocytes and foam-cell macrophages. Sex-specific cell-cell interaction analysis demonstrated increased VSMC-to-stromal interactions and elevated macrophage-macrophage signaling in male and female unstable plaques, respectively. Through spatial transcriptomics, inflammatory synthetic VSMCs identified by single-cell RNA sequencing dominated the lipid core in both male and female unstable plaques. However, only in males did these cells also replace the fibrotic cap, forming immune-rich niches among themselves and with macrophage-like VSMCs. CONCLUSIONS: Overall, these findings uncover distinct cellular and spatial mechanisms driving plaque destabilization in males and females, highlighting the need for sex-specific approaches to the diagnosis and treatment of carotid atherosclerosis.
Immune Mechanisms of Heart Valve Development, Homeostasis, and Disease.
Gonzalez BA, Yutzey KE
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42165146 · Full text
Valvular heart disease is among the most common cardiovascular conditions, usually presenting as aortic stenosis or mitral regurgitation. Clinically significant structural and functional anomalies can arise through conge...
Valvular heart disease is among the most common cardiovascular conditions, usually presenting as aortic stenosis or mitral regurgitation. Clinically significant structural and functional anomalies can arise through congenital malformation, genetic variants, cardiovascular dysfunction, infectious disease sequelae, or chronic inflammation that can progress over time, necessitating surgical replacement or repair. The most common types of valve disease requiring surgical intervention are mitral valve prolapse, often with myxomatous changes due to congenital malformation or infectious disease, and aortic valve stenosis resulting from calcific aortic valve disease. Recent studies have identified critical contributions of immune cells to aortic and mitral valve pathophysiology. Moreover, preclinical studies demonstrate valve disease mechanisms related to innate or adaptive immune cell infiltration that could be targeted in human valvular heart disease using existing or emerging anti-inflammatory approaches. Here, we review recent findings of immune cell contributions and molecular mechanisms of myxomatous valve disease, rheumatic heart disease, and calcific aortic valve disease with potential therapeutic applications.
CCR2 Neutrophils Exhibit a Proinflammatory Phenotype and Contribute to Plaque Vulnerability.
Farjia M, Pan C, Braster Q … +9 more , Lemnitzer P, Sachs N, Vöcking LM, Chevre R, Malamud M, Schulz C, Maegdefessel L, Soehnlein O, Silvestre-Roig C
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131921 · Publisher ↗
BACKGROUND: Atherosclerotic plaque destabilization is promoted by inflammatory cell recruitment, tissue cell death, and mechanical weakening. Neutrophils drive vascular tissue injury and perpetuate inflammation and repre...
BACKGROUND: Atherosclerotic plaque destabilization is promoted by inflammatory cell recruitment, tissue cell death, and mechanical weakening. Neutrophils drive vascular tissue injury and perpetuate inflammation and represent a viable therapeutic opportunity. Here, we identify a distinct subset of activated neutrophils within atherosclerotic lesions that express the chemokine receptor CCR2 (C-C chemokine receptor type 2), which directs their migration toward areas enriched with smooth muscle cells and contributes to plaque instability. METHODS: Flow cytometry and single-cell transcriptomic analysis of CCR2 neutrophils within murine and human atherosclerotic plaques. Tracking of CCR2 neutrophil in hypercholesterolemic mice and in mice reconstituted with bone marrow. In vivo reactive oxygen species and neutrophil extracellular trap analysis in lipopolysaccharide-induced peritonitis. In vitro migration assays of neutrophils deficient for or treated with a specific antagonist against chemokine receptors. In vivo neutrophil recruitment and features of atherosclerotic plaque vulnerability analysis on CCR2 and CCL2 (C-C motif chemokine ligand 2) blockade in a model of advanced atherosclerosis in mice. RESULTS: CCR2 neutrophils preferentially populate mouse and human atherosclerotic lesions and display a proinflammatory phenotype with enhanced capacity for reactive oxygen species production and neutrophil extracellular trap release. Genetic or pharmacological CCR2 inhibition reduced neutrophil migration and infiltration to the atherosclerotic lesion, reducing their presence in smooth muscle cell-rich areas. Consistently, neutralization of the CCR2 ligand CCL2 decreased lesional neutrophil numbers and preserved fibrous cap integrity by increasing smooth muscle cell content and decreasing features associated with plaque instability. CONCLUSIONS: Our data suggest that a subset of CCR2-expressing neutrophils senses smooth muscle cell-derived CCR2 ligands to infiltrate and promote vulnerable atherosclerotic lesions. These results support that neutrophil functional heterogeneity within the atherosclerotic lesions alters lesion stability. Specific targeting thereof may improve plaque stability without impacting host defense.
Efficacy of the Shear Stress Pattern Computed in Coronary Artery Reconstruction Models With and Without Side Branches in Predicting Plaque Progression.
Ramasamy A, Sivananthan A, Tanboga IH … +21 more , S M TK, Mohammed A, Hadjiandreou M, Sakellarios A, Kitslaar P, Dijkstra J, Kakizaki R, Crake T, Michalis LK, Ueki Y, Fotiadis D, Häner J, Losdat S, Otsuka T, Koskinas KC, Zhang YJ, Mathur A, Baumbach A, Torii R, Räber L, Bourantas CV
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131920 · Publisher ↗
BACKGROUND: The incorporation of side branches in vessel geometry influences wall shear stress (WSS) distribution. However, complete vessel reconstruction is time-consuming, and there is no evidence that its WSS estimati...
BACKGROUND: The incorporation of side branches in vessel geometry influences wall shear stress (WSS) distribution. However, complete vessel reconstruction is time-consuming, and there is no evidence that its WSS estimations better predict atherosclerotic disease progression compared with the output of the conventional single-vessel reconstruction (SVR). METHODS: Patients who had baseline and 1-year follow-up intravascular ultrasound imaging (n=40 vessels), and patients with neoatherosclerotic lesions (n=13 vessels) on optical coherence tomography were included. All the studied vessels had at least one side branch with a diameter >1 mm; 3-dimensional complete vessel reconstruction and SVR were performed, and the time-averaged WSS and multidirectional WSS were computed. The performance of both methods in predicting disease progression in intravascular ultrasound and optical coherence tomography models was assessed. RESULTS: The incorporation of side branches in 3-dimensional geometry resulted in lower minimum predominant time-averaged WSS in the intravascular ultrasound (1.09 versus 1.58 Pa, <0.001) and optical coherence tomography-based reconstructions (0.68 versus 1.33 Pa, <0.001) and influenced the multidirectional WSS distribution. In native segments, complete vessel reconstruction-derived WSS metrics demonstrated superior predictive performance for disease progression-defined as lumen area reduction and plaque burden increase-compared with SVR, as evidenced by improved out-of-sample accuracy (leave-one-out information criterion: 429 versus 551), discrimination (C statistic: 0.725 versus 0.651), calibration (Brier score: 0.172 versus 0.226), and explained variance (27.8% versus 20.7%). Consistent findings were observed in stented segments, where complete vessel reconstruction-derived WSS metrics more accurately predicted neointimal proliferation than SVR-derived metrics. CONCLUSIONS: Incorporating side branches into vessel reconstruction influences WSS distribution and enables more accurate prediction of atherosclerotic disease progression in native and stented segments than SVR.
Prelamin A in an Mouse Model Does Not Promote Atherosclerosis or Vascular Smooth Muscle Loss.
Wang Y, Joseph LC, Östlund C … +4 more , Kuriakose G, Hsu W, Michaelis S, Worman HJ
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131919 · Full text
BACKGROUND: Hutchinson-Gilford progeria syndrome is an accelerated aging disorder characterized by numerous symptoms, including early onset atherosclerosis, myocardial infarctions, and strokes. Hutchinson-Gilford progeri...
BACKGROUND: Hutchinson-Gilford progeria syndrome is an accelerated aging disorder characterized by numerous symptoms, including early onset atherosclerosis, myocardial infarctions, and strokes. Hutchinson-Gilford progeria syndrome is caused by mutations in that lead to expression of an internally truncated, farnesylated prelamin A variant called progerin, which induces loss of vascular smooth muscle cells. Some studies have also reported that accumulation of full-length farnesylated prelamin A, which is normally completely processed to mature nonfarnesylated lamin A, can also drive vascular pathology during physiological aging. METHODS: To assess the effects of prelamin A expression on atherosclerosis and aortic media vascular smooth muscle cells, we used mice that express a prelamin A variant with a lysine to arginine point mutation that prevents its processing to mature lamin A. We previously demonstrated bone defects, reduced body fat, and low body mass in these mice, similar to Hutchinson-Gilford progeria syndrome model mice. To determine if prelamin A expression has an impact on atherosclerotic plaques, we crossed mice to low-density lipoprotein receptor-deficient mice that develop hyperlipidemia on a high-fat diet. RESULTS: Atherosclerotic plaque lesion area and necrotic core area were not different in hyperlipidemic mice that expressed only prelamin A, and no mature lamin A, compared with hyperlipidemic mice that expressed only fully processed mature lamin A and no prelamin A. Additionally, exclusive prelamin A expression did not result in loss of aortic vascular smooth muscle cells or adventitial thickening in hyperlipidemic mice with atherosclerosis at 28 weeks of age. Indeed, aortic vascular smooth muscle remained normal in older mice at 52 weeks of age. There were no differences in proliferation or apoptosis of aortic media cells. CONCLUSIONS: In contrast to the prelamin A variant progerin expressed in Hutchinson-Gilford progeria syndrome, prelamin A does not appear to cause vascular smooth muscle loss, promote atherosclerosis, or drive vascular aging in mice.
SAHH Deficiency Decreases Stability of Atherosclerotic Plaque and Induces VSMC Phenotype Switching via Epigenetic Upregulation of KLF4 and OCT4.
Liu S, Huang T, Pan M … +8 more , Wang Y, Dai X, Liu C, Huang H, Ling W, Li B, He Y, Xiao Y
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131918 · Publisher ↗
BACKGROUND: -adenosylhomocysteine (SAH) is a novel risk factor of cardiovascular disease. SAHH (-adenosylhomocysteine hydrolase) inhibition leads to SAH accumulation and promotes the formation and development of atherosc...
BACKGROUND: -adenosylhomocysteine (SAH) is a novel risk factor of cardiovascular disease. SAHH (-adenosylhomocysteine hydrolase) inhibition leads to SAH accumulation and promotes the formation and development of atherosclerosis. However, the role and underlying mechanism of SAHH in the stability of advanced atherosclerotic plaque are still unknown. METHODS: ApoE-deficient mice with heterozygous SAHH knockout or vascular smooth muscle cell (VSMC)-specific or macrophage-specific SAHH knockout were used to investigate the effect of SAHH deficiency on atherosclerotic plaque stability. RESULTS: Heterozygote or VSMCs-specific but not macrophage-specific knockout of SAHH induced VSMC phenotype switching and decreased plaque stability. Whole-genome bisulfite sequencing and RNA sequencing showed that hypomethylation and upregulation of KLF4 (Krüppel-like factor 4) might be associated with SAHH deletion-induced VSMC phenotype switching. Mechanistically, SAHH deficiency resulted in SAH accumulation and induced KLF4 upregulation by inhibiting DNMT (DNA methyltransferase) 3b and leading to hypomethylation of the KLF4 promoter. Furthermore, SAHH deletion reactivated OCT4 (octamer-binding transcription factor 4)-mediated VSMCs migration in a KLF4-dependent manner via TET (tetmethylcytosine dioxygenase) 1-mediated hydroxymethylation of OCT4 promoter. In addition, SAHH deletion resulted in downregulation of TET2-mediated hydroxymethylation of the KLF4 promoter via inhibition of AMPK (AMP-activated protein kinase). Finally, decreased SAHH activity and elevated SAH levels were associated with unstable atherosclerotic plaque in patients with coronary artery disease or ischemic stroke. CONCLUSIONS: These results suggest that SAHH deficiency decreased the stability of atherosclerotic plaques and induced VSMC phenotype switching via epigenetic upregulation of KLF4 and OCT4.
Abdominal Fat Measures Are Associated With Sex-Specific Prothrombotic Changes in Middle-Aged Adults.
Verlaan JPL, Scheres LJJ, Rosendaal FR … +7 more , Gerdes VEA, Lamb HJ, Morelli VM, Lisman T, de Mutsert R, Cannegieter SC, van Hylckama Vlieg A
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131917 · Publisher ↗
BACKGROUND: A high body mass index is an important risk factor for venous thromboembolism. However, high body mass index does not necessarily reflect an unhealthy body fat distribution. Therefore, we evaluated the associ...
BACKGROUND: A high body mass index is an important risk factor for venous thromboembolism. However, high body mass index does not necessarily reflect an unhealthy body fat distribution. Therefore, we evaluated the association between the amount of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue, and liver fat content with venous thromboembolism-associated coagulation parameters: plasma levels of factor (F) VIII, FIX, FXI, fibrinogen, and thrombin generation (endogenous thrombin potential and peak thrombin). METHODS: In 1759 participants of the NEO study (the Netherlands Epidemiology of Obesity), VAT and abdominal subcutaneous adipose tissue were assessed with magnetic resonance imaging, and liver fat with H-MR spectroscopy. Through linear regression, we examined cross-sectional associations between quartiles of body fat measures and coagulation parameters, stratified by sex and adjusted for relevant confounders. RESULTS: We found that the amount of VAT was associated with all coagulation parameters in a dose-response manner, with higher levels for individuals in quartile 4 versus 1, ranging between 5.2% (95% CI, -5.8 to 17.4) for FVIII in men and 21.0% (95% CI, 16.7-25.5) for FIX in women. In women, the amount of abdominal subcutaneous adipose tissue was associated with all coagulation parameters, with the highest percentual difference between quartile 4 versus 1 for endogenous thrombin potential 25.4% (95% CI, 13.7-38.4). Liver fat was mostly associated with higher FIX in both sexes, 13.2% (95% CI, 8.6-18.0) in men and 13.6% (95% CI, 10.0-17.4) in women. CONCLUSIONS: The strongest prothrombotic associations were found for VAT. Abdominal subcutaneous adipose tissue contributed only in women, though less strongly than VAT, indicating sex-specific associations. Liver fat was consistently associated with FIX. These findings underscore the importance of body fat distribution and sex in coagulation and thrombotic potential.
PERK Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis.
Zhu LY, Xue C, Bashore AC … +11 more , Cui J, Yao S, Sachs N, Wettich JL, Coronel J, Garcia EJ, Khalid S, Saleheen D, Li M, Maegdefessel L, Reilly MP
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42131916 · Full text
BACKGROUND: Smooth muscle cell (SMC)-derived cells form the bulk of cells in atherosclerotic lesions and modulate lesion stability and cardiovascular disease outcomes. Unfolded protein response (UPR) markers, thin fibrou...
BACKGROUND: Smooth muscle cell (SMC)-derived cells form the bulk of cells in atherosclerotic lesions and modulate lesion stability and cardiovascular disease outcomes. Unfolded protein response (UPR) markers, thin fibrous caps, and inflammation correlate with human lesion instability and rupture. In mice, UPR drives macrophage and endothelial apoptosis and inflammation, but its impact on lesion stability through SMC modulation is debated. The UPR protein PERK (protein kinase RNA-like ER kinase) was recently shown to drive SMC modulation in vivo, suggesting that depletion of SMC Perk may regulate lesion stability. METHODS: SMC Perk was deleted from SMC-lineage-traced adult Ldlr hypercholesterolemic mice. Lesions were scored for features of lesion stability and analyzed for differential expression at the single-cell level. Perk knockdown in primary murine SMCs was used to study Perk's effect on SMC modulation in vitro. Human carotid lesions were assessed for UPR markers through scRNA-seq, bulk RNA-seq, and Xenium spatial transcriptomics. RESULTS: SMC Perk deletion in adult atherogenic mice did not affect weight gain or serum cholesterol levels. Lesions from Perk knockout mice resembled Perk WT counterparts with similar progression, lesion stability features, and cell populations. Scoring of UPR markers and differential expression analysis found little UPR activity in SMC and smooth muscle-derived cell populations. Perk was not required for in vitro SMC modulation in atherogenic conditions. No correlation was found between UPR markers and lesion stability or symptomatic clinical presentation in human carotid lesions, and UPR markers were expressed primarily in infiltrating leukocytes rather than in SMCs and stromal cells. CONCLUSIONS: SMC Perk UPR does not play a significant role in atherosclerotic SMC modulation, disease progression, or features of lesion stability in mice. Similarly, expression of markers of the Perk UPR pathway in humans does not correlate with human carotid lesion stability or clinical presentation.
Integrated Single-Cell Atlas Reveals Cross-Subtype Heterogeneity in Human Pulmonary Hypertension.
Feng H, Lai J, Yang X … +9 more , Cui X, Mo S, Feng Y, Chen Q, Zhong B, Lu W, Chen Y, Yang K, Wang J
Arterioscler Thromb Vasc Biol · 2026 May · PMID 42131915 · Publisher ↗
BACKGROUND: Pulmonary hypertension (PH) is a severe vascular disorder characterized by pathological pulmonary vascular remodeling. Although single-cell RNA sequencing has provided insights into PH, patient studies remain...
BACKGROUND: Pulmonary hypertension (PH) is a severe vascular disorder characterized by pathological pulmonary vascular remodeling. Although single-cell RNA sequencing has provided insights into PH, patient studies remain fragmented across clinical subtypes and are processed with heterogeneous pipelines, limiting cross-study comparability and integrative interpretation of disease-relevant cellular states in human PH. METHODS: We integrated single-cell RNA sequencing data sets to construct a core PH-specific cellular atlas using a standardized quantification and batch-correction pipeline, followed by hierarchical cell type annotation to define major lineages and finer cell states. We then performed comparative analyses to reassess reported cellular alterations within a unified reference. Building on this atlas, we developed PH-Map, a multitask learning tool pretrained on this atlas for rapid hierarchical cell annotation and validated it in independent external cohorts. RESULTS: The core PH-specific atlas comprises 235 621 high-quality cells from 64 human samples spanning idiopathic pulmonary arterial hypertension, systemic sclerosis-associated pulmonary arterial hypertension, chronic thromboembolic PH, and healthy controls, organized into 6 major lineages and 58 distinct cell states. Cross-subtype comparison revealed shared and subtype-specific remodeling across vascular and immune compartments, including redefined smooth muscle cell states, fibroblast-associated complement activation in idiopathic pulmonary arterial hypertension, and heterogeneous immune transcriptional programs. We additionally observed system-dependent differences, including variable major histocompatibility complex class II activation in capillary endothelial cells across animal models versus human PH and convergent phenotypic shifts in primary cultured endothelial cells relative to native lung endothelial cells. PH-Map showed stable hierarchical annotation performance in external cohorts across multiple levels of annotation granularity with improved computational efficiency. CONCLUSIONS: This core human single-cell PH atlas enables systematic cross-subtype comparison and delineates shared and subtype-specific cellular programs across vascular and immune compartments. Together with PH-Map, it supports reproducible hierarchical annotation and prioritization of candidate cell states and pathways for downstream studies.
Saturated and Unsaturated Fat-Based Ketogenic Diets Attenuate Atherosclerosis Despite Divergent Effects on Adiposity.
Li X, Abdualkader AM, Lacroix E … +4 more , Bai C, Pourfarziani P, Martel C, Al Batran R
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42093642 · Publisher ↗
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Mitochondrial Extracellular Vesicles Enhance Aortic Valve Calcification Via Carnitine O-Octanoyltransferase-Brief Report.
Itagawa R, Okui T, Tanaka T … +11 more , Nakamura Y, Hosokawa D, Clift CL, Blaser MC, Kasai T, Weiss L, Turner ME, Billaud M, Aikawa M, Singh SA, Aikawa E
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42093641 · Full text
BACKGROUND: Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator...
BACKGROUND: Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator of mitochondrial dysfunction and vascular calcification; however, its role in calcific aortic valve disease is unknown. We investigated whether CROT promotes calcific aortic valve disease progression through the release of procalcific mitochondria-derived extracellular vesicles (mitoEVs). METHODS: Human valvular interstitial cells were isolated from aortic valves of patients with aortic stenosis (n=49; n=34 males, n=15 females). Calcification was induced with osteogenic medium and assessed by Alizarin red. Proteomics compared valvular interstitial cells cultured in normal medium or osteogenic medium following scramble or siRNA to define CROT-dependent pathways. Mitochondrial function was evaluated by Seahorse XF analysis (oxygen consumption rate) and morphology by MitoTracker staining. Extracellular vesicles were isolated by ultracentrifugation and characterized using NanoSight Pro. In vivo, aortic stenosis was induced by aortic valve wire injury in (Sham, n=12; aortic valve wire injury, n=19) and (aortic valve wire injury, n=23) mice. Disease progression was monitored by echocardiography, and calcification was visualized using OsteoSense680EX imaging. RESULTS: CROT silencing significantly reduced osteogenic medium-induced calcification in valvular interstitial cells (<0.05). Proteomics revealed alterations in mitochondria-associated proteins following siCROT. Osteogenic medium-induced mitochondrial fragmentation and increased mitoEV release were attenuated by CROT silencing. Immunofluorescence revealed mitoEVs localized to calcified extracellular regions. In vivo, CROT deficiency reduced valvular calcification and attenuated aortic stenosis progression. CONCLUSIONS: Osteogenic stress drives mitochondrial fragmentation and procalcific mitoEV release. CROT inhibition restores mitochondrial homeostasis, reduces mitoEV release and calcification, identifying CROT as a potential therapeutic strategy for calcific aortic valve disease.
Neurological Impact of Caplacizumab in Refractory iTTP Survivors: A Comparative Study of Blood-Brain-Barrier Integrity and Cognitive Outcomes.
Hannan F, Thiessen JD, Patriquin CJ … +9 more , Pavenski K, Tristao L, Lee TY, Mendes D, Théberge J, Mandzia JL, Al-Jaishi M, Gallo KL, Huang SS
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42093640 · Publisher ↗
BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) causes systemic microvascular thrombosis, often leading to long-term neurological complications and cognitive decline despite achieving hematologic r...
BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) causes systemic microvascular thrombosis, often leading to long-term neurological complications and cognitive decline despite achieving hematologic remission. Persistent blood-brain barrier (BBB) dysfunction is a suspected driver of these chronic sequelae. This study investigated whether adding caplacizumab to standard of care (SOC) improves long-term BBB integrity and cognitive outcomes in refractory iTTP survivors compared with SOC alone. METHODS: We analyzed 16 patients with iTTP categorized into SOC-only (n=7) or SOC plus caplacizumab (n=9) cohorts. Patients underwent computed tomography perfusion imaging to measure BBB permeability (PS product), blood flow, and blood volume at baseline (30 days postremission) and 12-month follow-up. Cognitive function was assessed using Creyos (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03187652). RESULTS: At baseline, the caplacizumab group, composed largely of refractory cases, exhibited nominally higher BBB permeability than the SOC-only group (0.48±0.11 mL/min per 100 grams versus 0.38±0.14 mL/min per 100 grams, =0.048, Cohen d=0.73 [95% CI, -0.277 to -0.001]), an exploratory finding. The primary outcome, within-group BBB-PS reduction in the SOC plus caplacizumab group at 12 months, was significant (0.37±0.09 mL/min per 100 grams, =0.027, Cohen d=0.90 [95% CI, 0.016-0.203]), while the SOC-only group showed minimal change. Despite variations in rituximab administration due to regional funding restrictions, higher BBB permeability was moderately to strongly correlated with lower scores across all cognitive domains and lower ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13) activity (<0.05, Benjamini-Hochberg corrected). CONCLUSIONS: Caplacizumab may provide a neuroprotective benefit by facilitating BBB repair, even in initially refractory patients. These findings suggest that targeting microvascular integrity during acute episodes can mitigate long-term cognitive decline in iTTP survivors. By facilitating long-term BBB repair, caplacizumab may mitigate chronic cognitive decline and improve the quality of life for refractory iTTP survivors.
Thrombus and Aortic Wall F-FDG Positron Emission Tomography Uptake in Abdominal Aortic Aneurysms.
Bragulat-Arévalo M, Guala A, Ferrer-Cornet M … +9 more , García-Reyes M, Garrido-Oliver J, Oliveró-Soldevila R, Catala-Santarrufina A, Lopez-Gutierrez P, Ferreira-González I, Rodríguez-Palomares J, Bellmunt-Montoya S, Dux-Santoy L
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42093639 · Publisher ↗
BACKGROUND: Most abdominal aortic aneurysms (AAA) present intraluminal thrombus (ILT). Whether its role is detrimental or protective for AAA evolution and patients outcomes is debated. F-fluorodeoxyglucose positron emiss...
BACKGROUND: Most abdominal aortic aneurysms (AAA) present intraluminal thrombus (ILT). Whether its role is detrimental or protective for AAA evolution and patients outcomes is debated. F-fluorodeoxyglucose positron emission tomography analysis in patients with AAA has shown contradictory results and has not widely explored ILT. The aim of this cross-sectional study was to investigate the colocalized association between F-fluorodeoxyglucose and ILT presence and characteristics in AAA. METHODS: Consecutive patients with infrarenal AAA were prospectively enrolled and underwent positron emission tomography/magnetic resonance imaging. From the abdominal aorta segmentation, an aortic wall volume was defined and discretized into 28 standardized aortic patches, permitting colocalized interpatient and intrapatient analyses. The target-to-background ratio (TBR) was extracted in each patch, and extremely low (coldspots) and high (hotspots) absorption areas were computed. Local AAA diameters and ILT characteristics were computed in each patch. Linear mixed-effect models were used to test the association between AAA and ILT characteristics and F-fluorodeoxyglucose uptake. RESULTS: Thirty-six patients (median age, 73 [interquartile range, 68-77] years, 31 [86.1%] men) completed the protocol. The AAA maximum diameter was 49.6 (45.0-56.2) mm, and most patients (28 [77.8%]) presented ILT. Patients with thrombus presented higher coldspot area and lower hotspot area (<0.001). Patches in nondilated regions presented higher TBR compared with AAA patches (<0.001), which showed a negative association of TBR with local diameter (=-0.006) and thrombus presence (=-0.003). TBR decreased with increased ILT coverage (=-0.002), while coldspot area increased (=0.046). In both the ILT and thrombus-covered wall, TBR decreased with increasing ILT thickness. CONCLUSIONS: Decreased metabolic activity as per 18-fluorodeoxyglucose positron emission tomography is observed in the AAA wall compared with the nondilated abdominal region. This effect is exacerbated by local thrombus presence and thickness, suggesting that ILT contributes to the further degradation of the aortic wall in the diseased region.
Circulating Progenitor Cells, Regenerative Capacity and Cognition: Evidence From 2 Community-Based Cohorts.
Ahmed T, Gold M, Kulshreshtha A … +17 more , Woods E, Rahbar A, Hossain M, Ko YA, Medina-Inojosa J, Harris KA, Huang J, Maisuradze N, Owais M, Sakr SM, Thomas T, Goldstein F, Lah J, Waller E, Calhoun V, Quyyumi A, Hajjar I
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42093638 · Full text
BACKGROUND: Impaired endogenous vascular regenerative capacity, reflected by reduced circulating progenitor cell (CPC) counts, has been linked to age-related diseases, particularly adverse cardiovascular outcomes. Lower...
BACKGROUND: Impaired endogenous vascular regenerative capacity, reflected by reduced circulating progenitor cell (CPC) counts, has been linked to age-related diseases, particularly adverse cardiovascular outcomes. Lower CPC counts have also been associated with accelerated age-related cognitive decline in otherwise healthy individuals, but their relationships with cognitive impairment and neuroimaging markers of vascular brain injury and neurodegeneration remain unclear. We investigated cross-sectional associations between CPC subsets, cognitive performance, and neuroimaging phenotypes, hypothesizing that lower CPC levels would be associated with worse cognition and adverse brain markers. METHODS: In 283 community-dwelling participants (mean age, 65 years; 59% female, 39% Black) enrolled in the Brain Stress, Hypertension, and Aging Research Program, cognitive assessments (including Montreal Cognitive Assessment), brain magnetic resonance imaging-derived white matter hyperintensity volumes, and whole-brain cortical thickness were measured. Flow cytometry was used to enumerate CPCs as CD45 mononuclear cells expressing CD34 with coexpression of either CD133, chemokine CXCR4 (CXC motif receptor 4), or VEGFR2 (vascular endothelial growth factor receptor-2). Linear regression models were adjusted for demographic and vascular risk factors. RESULTS: In fully adjusted models, lower CD34/CD133 CPC levels were associated with worse global cognition (Montreal Cognitive Assessment: β=0.59; =0.01), lower mean cortical thickness (β=0.01; =0.01), and greater white matter hyperintensity burden (β=-0.15; =0.01). Similarly, lower CD34 and lower CD34/CXCR4 CPC levels were significantly associated with greater white matter hyperintensity volume (CD34: β=-0.27, <0.01; CD34/CXCR4+: β=-0.14, =0.03). CD34/VEGFR2 CPC levels were associated with Montreal Cognitive Assessment (β=0.37, <0.01) and Boston Naming Test performance (β=0.01, =0.03), but not with neuroimaging phenotypes. CONCLUSIONS: Reduced regenerative capacity was associated with worse global cognitive performance and markers of vascular brain injury, including greater white matter hyperintensity burden and cortical thinning. These findings should be validated in longitudinal studies to clarify temporality and potential causality.
Multiomics Analysis Reveals Stromal Cell State Changes and INHBA-Associated Remodeling in Calcific Aortic Valve Disease.
Jin S, Wu S, Shen F … +6 more , Meng C, Fan J, Shu M, Zhao D, Yang D, Yu M
Arterioscler Thromb Vasc Biol · 2026 Jul · PMID 42059080 · Publisher ↗
BACKGROUND: The cellular and molecular mechanisms underlying calcific aortic valve disease (CAVD) remain incompletely understood. Emerging evidence suggests that signaling components active during valve development may a...
BACKGROUND: The cellular and molecular mechanisms underlying calcific aortic valve disease (CAVD) remain incompletely understood. Emerging evidence suggests that signaling components active during valve development may also be relevant to disease-associated remodeling, although their context-specific roles remain unclear. METHODS: We integrated multiomics data, including genome-wide association study summary data, single-cell RNA sequencing from fetal, healthy adults, and CAVD valves, and bulk RNA-sequencing data sets to identify the CAVD-relevant cell populations and candidate genes. Then, an in vitro calcification model of valvular interstitial cells (VICs) was used to assess the role of (inhibin subunit βA) in VIC calcification and to examine its expression in an in vivo CAVD model. RESULTS: Our single-cell analysis revealed stage-associated changes in valve cell composition across fetal, healthy, and CAVD conditions. VICs and valve-derived stromal cells (VDSCs) showed closely connected transcriptional states. Specifically, fetal VIC subpopulations, including VIC3 and VIC5, shifted toward adult VIC2 and VDSC2, and ultimately toward VDSC1-enriched states in CAVD. VDSC1 was consistently enriched in CAVD and showed enrichment of inflammation-related and extracellular matrix remodeling-related pathways. Cell-cell communication analysis showed significantly enhanced interactions between VDSC1 and macrophages in CAVD, consistent with increased inflammatory signaling in the local microenvironment. Integrated analysis of genome-wide association study, bulk RNA sequencing, and single-cell RNA sequencing identified 21 candidate genes associated with CAVD. Among these, INHBA showed stage-dependent expression across valve conditions. In vitro, INHBA expression increased during osteogenic induction of VICs, along with elevated RUNX2 (runt-related transcription factor 2) and ALP (alkaline phosphatase), whereas silencing reduced calcification. In vivo, INHBA expression also differed across fetal, healthy, and calcified valves. CONCLUSIONS: Those findings define stage-associated shifts in VIC and VDSC subpopulations across valve conditions and identify VDSC1 enrichment as a prominent feature of CAVD. Our data further implicate in osteogenic remodeling of VICs and support further evaluation of in disease-associated remodeling in CAVD.
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