Arteriosclerosis, Thrombosis, And Vascular Biology[JOURNAL]
Sun
200 papers
PCPE1 and PCPE2: When Sequence Similarity Masks Functional Diversity.
Sorci-Thomas MG, Rocksvold A, Ahmad B
Arterioscler Thromb Vasc Biol · 2026 Jun · PMID 41953976 · Publisher ↗
PCPE1 (procollagen C-endopeptidase enhancer 1) and PCPE2 are ECM (extracellular matrix) glycoproteins that lack intrinsic protease activity and regulate procollagen processing. Initially, these glycoproteins were found t...
PCPE1 (procollagen C-endopeptidase enhancer 1) and PCPE2 are ECM (extracellular matrix) glycoproteins that lack intrinsic protease activity and regulate procollagen processing. Initially, these glycoproteins were found to be structurally related and assumed to play similar roles in enhancing collagen maturation. Recent evidence suggests that PCPE1 and PCPE2 exert both overlapping and distinct biological functions beyond collagen processing. PCPE1, first identified and shown to enhance collagen assembly in the ECM, now appears to be involved in adipose-to-liver crosstalk, angiogenesis, and fibrosis/wound healing. By comparison, PCPE2, with ≈45.6% amino acid identity (≈80.6% amino acid similarity) to PCPE1, inhibits PCPE1's enhancement of procollagen processing while also participating in cellular plasticity, innate immune responses, and adipose tissue expansion. Together, the evidence suggests that PCPE1 and PCPE2 exhibit functional overlap but also play additional regulatory roles beyond traditional ECM remodeling.
Endothelial Dysfunction in Preeclampsia: Focus on the Uteroplacental Circulation.
Tucker SM, Hula N, Gardner JJ … +1 more , Goulopoulou S
Arterioscler Thromb Vasc Biol · 2026 Jun · PMID 41953975 · Full text
Preeclampsia is a pregnancy disorder characterized by de novo maternal hypertension, end-organ damage, and fetal complications. It is also associated with increased long-term cardiovascular risk for both the mother and o...
Preeclampsia is a pregnancy disorder characterized by de novo maternal hypertension, end-organ damage, and fetal complications. It is also associated with increased long-term cardiovascular risk for both the mother and offspring. A general lack of understanding of this disease prevents effective treatment and prevention, with delivery of the fetoplacental unit being the current standard of care for severe cases. A hallmark characteristic of the maternal syndrome is endothelial dysfunction in both reproductive and nonreproductive vascular beds. As the uterine vascular bed serves as the interface between the maternal and fetal circulation, it is pivotal in the cardiovascular function of both mother and fetus. In this review, we highlight uterine artery endothelial maladaptation as a central feature of preeclampsia and discuss its anatomic, cellular, and circulating correlates.
Integrated Forward and Reverse Degradomics of Aortic Aneurysms Uncovers Their Proteolytic Landscapes and the Roles of MMP9 and Mast Cell Chymase.
Bhutada S, Martin DR, Cikach F … +10 more , Germano da Silva E, Willard BB, Ramkhelawon B, Chung MK, Dahal S, Ramamurthi A, Barnard J, Blackstone EH, Roselli EE, Apte SS
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41924878 · Publisher ↗
BACKGROUND: Dysregulated proteolysis is implicated in thoracic (thoracic aortic aneurysm [TAA]) and abdominal aortic aneurysm (AAA) pathogenesis, but proteolytic landscapes (degradomes) of aneurysmal and normal aorta and...
BACKGROUND: Dysregulated proteolysis is implicated in thoracic (thoracic aortic aneurysm [TAA]) and abdominal aortic aneurysm (AAA) pathogenesis, but proteolytic landscapes (degradomes) of aneurysmal and normal aorta and contributions of individual proteases remain undefined. Here, a proteome-wide approach was used to define and compare TAA and AAA degradomes and uncover the specific role in aortic remodeling of 2 proteases consistently identified in the aneurysms, CMA1 (mast cell chymase) and MMP9 (matrix metalloprotease 9). METHODS: The mass spectrometry-based N-terminomics strategy, terminal amine isotopic labeling of substrates, was applied to Marfan syndrome TAAs (n=5), AAAs (n=16), and nondiseased thoracic aorta (n=4), and abdominal aorta (n=4) in a forward degradomics application, that is, to define substrate and protease degradomes. 8-plex iTRAQ terminal amine isotopic labeling of substrates was used for quantitative comparison of the tissue cohorts. Cleavage sites of CMA1 and MMP9 were sought by reverse degradomics, that is, digestion of aortic proteins with these proteases, followed by terminal amine isotopic labeling of substrates. CMA1 and MMP9 proteolysis of biglycan was further resolved using amino-terminal oriented mass spectrometry of substrates. RESULTS: We experimentally annotated 20 885 proteolytically derived peptides and identified 129 proteases in the aortic tissues. Quantitative substrate degradome comparisons identified specific differentially modulated pathways and networks in TAAs and AAAs. Reverse degradomics elucidated >300 CMA1 and MMP9 substrate cleavage sites, of which many, including orthogonally validated biglycan cleavages, occurred in the disease degradomes. CONCLUSIONS: Unbiased forward degradomics of the aortic wall from TAA, AAA, and nondiseased tissue provides a systems biology view of aortic wall breakdown and a new resource for its hitherto occult proteolytic landscape, demonstrating widespread extracellular matrix remodeling with disproportionate impact on proteoglycans. The findings provided insights into aortic aneurysm pathways and disease biomarkers and suggest involvement of numerous proteases. Mapping of specific proteolytic contributions of CMA1 and MMP9 illustrates a strategy for defining the activities of all proteases involved in aortic disease.
Activin A-Endothelin-1 Axis Governs Pulmonary Vascular Remodeling: Mechanistic Basis for Emerging Therapies in PAH.
Faizah NN, Ryanto GRT, Kencana SMS … +4 more , Suzuki Y, Hara T, Otake H, Emoto N
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41924877 · Full text
BACKGROUND: Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied...
BACKGROUND: Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied by vasoactive mediators imbalance such as ET-1 (endothelin-1). Although endothelin receptor antagonists alleviate vasoconstriction, they incompletely address the remodeling process. We previously reported how endothelial-derived activin A promotes vascular remodeling, leading to the clinical development of the activin signaling inhibitor sotatercept, which improves outcomes when added to endothelin receptor antagonists. As both activin A and ET-1 originate from endothelial cells and promote remodeling, we investigated whether activin A regulates ET-1 production and activity in pulmonary arterial hypertension. METHODS: In vitro, we used pulmonary artery endothelial cell models of activin A overabundance alone or cocultured with pulmonary artery smooth muscle cells. Cells were treated with either the activin A inhibitor FST (follistatin), the endothelin receptor antagonist bosentan, the FST/bosentan combination, or vehicle for analysis. In vivo, we exposed wild-type or endothelial-specific INHBA (inhibin β-A)-overexpressing mice (VEcadherin-INHBA-Transgenic/VEcad-INHBA-Tg) to chronic hypoxia pulmonary hypertension model, with the addition of FST, bosentan, FST and bosentan, or vehicle treatments after the first week of hypoxia exposure. RESULTS: Activin A upregulated ET-1 expression via canonical SMAD2/3 (small mother against decapentaplegic family member 2/3) signaling in pulmonary artery endothelial cells. This induction, as well as ET-1-driven downstream effects-including reduced eNOS (endothelial NO synthase), pulmonary artery smooth muscle cell phenotypic switching, oxidative stress, and endothelial-to-mesenchymal transition-was reversed by FST alone or in combination with bosentan. In vivo, FST-based therapy achieved greater hemodynamic, right ventricular remodeling, and vascular structural normalization in wild-type and VEcad-INHBA-Tg mice than bosentan alone, accompanied by stronger ET-1 suppression. CONCLUSIONS: We identified ET-1 as a downstream effector of activin A in pulmonary arterial hypertension development, supporting activin A blockade as a strategy to inhibit ET-1-mediated vasoconstriction and remodeling. This mechanistic link provides a rationale for the rapid clinical benefits observed with sotatercept and suggests its potential role earlier in the pulmonary arterial hypertension treatment paradigm.
Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.
Tsitsipatis D, Rodriguez Rivera T, Kaileh M … +6 more , Okereke AN, Gupta A, Singh A, Raph SM, Henry-Smith C, Herman AB
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41924876 · Full text
BACKGROUND: This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions. METHODS: We measured the cap...
BACKGROUND: This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions. METHODS: We measured the capacity of senescent VSMCs for scavenging oxLDL (oxidized low-density lipoprotein), which was impaired in senescent cells compared with proliferating and quiescent cells. Next, we obtained human peripheral blood monocytes from people >60 years old and differentiated them into macrophages using GM-CSF (granulocyte-macrophage colony-stimulating factor). We treated the macrophages with conditioned media derived from proliferating, quiescent, and senescent VSMCs and measured oxLDL uptake, phagocytosis, and efferocytosis. RESULTS: The results demonstrated that macrophages treated with senescent VSMC conditioned media experienced impaired oxLDL uptake, phagocytic activity, and reduced ability to clear senescent cells. Treatment of senescent VSMCs with senomorphic drugs before conditioned media transfer restored macrophage functions, confirming that the SASP (senescence-associated secretory phenotype) is critical for impairing macrophages during atherosclerotic conditions. CONCLUSIONS: Our results suggest that the SASP derived from senescent VSMCs prevents foam cell formation and disrupts the homeostatic function of macrophages in atherosclerosis. By suppressing macrophage function, senescent cells seem to evade immune clearance and accumulate, further propagating disease development.
ILK-Dependent Modulation of DPP4 Prevents Progression of Calcific Aortic Valve Disease.
Delgado-Marín M, Sánchez-Esteban S, Cook-Calvete A … +6 more , Castro-Pinto M, López-Menendez J, Hernandez I, Zamorano JL, Zaragoza C, Saura M
Arterioscler Thromb Vasc Biol · 2026 Jun · PMID 41924875 · Full text
BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by endothelial dysfunction, fibrosis, and osteogenic calcification, yet the molecular mechanisms driving disease progression remain incompletely understoo...
BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by endothelial dysfunction, fibrosis, and osteogenic calcification, yet the molecular mechanisms driving disease progression remain incompletely understood, and no pharmacological therapies are currently available. Reduced endothelial ILK (integrin-linked kinase) expression has been implicated in CAVD, but its downstream effectors remain undefined. METHODS: To explore the direct role of ILK in CAVD development, we used a mouse model in which ILK is conditionally deleted from endothelial cells (endothelial cell-specific ILK conditional knockout). DPP4 (dipeptidyl peptidase 4) expression and activity were examined in human aortic valve tissue and plasma from patients with and without CAVD as a potential therapeutic target. Mechanistic studies were performed in human valvular endothelial cells subjected to ILK silencing, with or without pharmacological or genetic DPP4 inhibition. In vivo, endothelial cell-specific ILK conditional knockout mice were treated with the DPP4 inhibitor sitagliptin, and valvular, cardiac function, and remodeling were assessed. RESULTS: DPP4 expression was increased in circulation and in the aortic valves of patients with CAVD and was inversely correlated with ILK levels, with predominant localization to valvular endothelial cells. ILK silencing in human valvular endothelial cells increased DPP4 expression and enzymatic activity, promoted endothelial-to-mesenchymal transition, and induced osteogenic reprogramming; these effects were attenuated by DPP4 inhibition. Endothelial ILK deletion in mice recapitulated CAVD features, including inflammation, valve thickening, calcification, and cardiac remodeling, all of which were associated with increased DPP4. Sitagliptin treatment mitigated disease severity. Mechanistically, sitagliptin inhibited NF-κB (nuclear factor kappa B)-driven DPP4 upregulation caused by ILK loss. CONCLUSIONS: These findings identify DPP4 as a key downstream effector linking endothelial ILK deficiency to inflammation, endothelial-to-mesenchymal transition, and calcific remodeling in CAVD and support DPP4 inhibition as a potential disease-modifying strategy to slow disease progression.
Proteogenomic Analysis of Coronary Artery Calcification in Human Populations.
El-Sabawi B, Huang X, Lin P … +28 more , Anwar MY, Betti M, Kim N, Perry AS, Perera BLA, Gajjar P, Colangelo LA, Amancherla K, Sheng Q, Zhao S, Stolze LK, Farber-Eger E, Landman JM, Miller PE, Liu GY, Das S, Wells QS, Terry JG, Lloyd-Jones D, Das S, Khan SS, North KE, Below J, Nayor M, Kalhan R, Carr JJ, Gamazon ER, Shah RV
Arterioscler Thromb Vasc Biol · 2026 Jun · PMID 41924874 · Full text
BACKGROUND: Joint use of multiple molecular layers can be useful to prioritize targets for mechanistic studies. Application of this approach to coronary disease in large populations is an emerging field. METHODS: We used...
BACKGROUND: Joint use of multiple molecular layers can be useful to prioritize targets for mechanistic studies. Application of this approach to coronary disease in large populations is an emerging field. METHODS: We used reported circulating proteomic data (Somascan aptamer-based) from ≈3000 individuals in the CARDIA study (Coronary Artery Risk Development in Young Adults), measuring association with prevalent and 10-year incident coronary artery calcium (CAC) score. We used a multiparametric approach to prioritize circulating protein-CAC associations via genomics of circulating protein levels and coronary artery transcription. RESULTS: Proteins linked to prevalent/incident CAC in CARDIA implicated pathogenic mechanisms of vascular disease, including fibrosis and inflammation (GDF-15 [growth/differentiation factor 15], CDCP1 [CUB domain-containing protein 1], GSN [gelsolin], THBS2 [thrombospondin-2], chemokines, RNAS6 [ribonuclease K6]), oxidative lipid metabolism (CILP2; cartilage intermediate layer protein 2), extracellular matrix remodeling and signaling (MMPs [matrix metalloproteinases], TIMP-1 [tissue inhibitor of metalloproteinases 1], integrins), calcification (Notch 1, ARHGAP36 [Rho GTPase-activating protein 36]), and metabolism (GIP [gastric inhibitory polypeptide]), as well as new proteins not previously reported. Using proteome-wide association study genetic approaches, several targets with nominal evidence in CAC proteomics were associated with atherosclerosis or myocardial infarction in over 300K individuals, including PCSK9 (proprotein convertase subtilisin/kexin type 9) and APOC1. Finally, the coronary artery-specific transcriptome-wide association study of CAC yielded genes with previously implicated mechanistic roles in vascular homeostasis, inflammation, and metabolism, as well as genes without previously described function in CAC. Overlap across CAC proteomics and transcriptome-wide association study highlighted genes involved in vascular inflammation (S100A9), cardiac development (HES1 [transcription factor HES-1]), vessel wall structure (SPARCL1 [SPARC-like protein 1]), and vascular dysfunction or plaque (NOTCH3 [neurogenic locus notch homolog protein 3], TNFSF12 [tumor necrosis factor ligand superfamily member 12], S100A12 [protein S100-A12]). CONCLUSIONS: These results report population-level multiomics in human coronary calcification, presenting a method to identify disease-relevant targets through integration of human genetic approaches with multiomics.
Safety and Treatment Efficacy of Systemic, Locoregional, and Nanoparticle Encapsulated Anthracycline Chemotherapy: Insights Into Cardiotoxicity.
Hammond ST, Brandt L, Kong AL … +3 more , White SB, Lewandowski D, Beyer AM
Arterioscler Thromb Vasc Biol · 2026 Jun · PMID 41924873 · Full text
Cancer survivors are at an increased risk for major adverse cardiovascular events and cardiovascular disease mortality compared with the general population. In fact, emerging evidence suggests that cardiovascular disease...
Cancer survivors are at an increased risk for major adverse cardiovascular events and cardiovascular disease mortality compared with the general population. In fact, emerging evidence suggests that cardiovascular disease is the leading cause of mortality 10 years into survivorship for some cancer populations. While this heightened cardiovascular risk undoubtedly involves a variety of factors, antineoplastic therapies, such as anthracyclines, are known to contribute significantly to this pathology. As such, modalities that improve the localization of treatments to the tumor while simultaneously minimizing off-target effects on noncancerous cells are greatly needed. Approaches in which anthracyclines are injected directly into tumor-feeding arterioles (locoregional/intra-arterial administration) or are encapsulated in tumor-directed nanoparticles have gained prominence in certain cancers. Such therapies should direct cardiotoxic chemotherapy away from sites of potential toxicity while leaving the tumor exposed. However, current clinical findings on the efficacy and cardiovascular safety of these treatments remain inconclusive, and their use for many cancers is limited. This narrative review aims to highlight current clinical findings that have evaluated the safety and efficacy of locoregional and nanoparticle-mediated anthracycline administration as they compare with systemic delivery and identify avenues to be explored by future research.
PPI-Clopidogrel Interaction: Can Claims Data Settle the Debate?
Navarese EP, Tantry US, Jeong YH … +1 more , Gurbel PA
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884899 · Publisher ↗
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Lymphatic Malformations With Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix Metalloproteinases.
Mastrogiacomo DM, Price A, Fu Y … +7 more , Banerjee R, Knauer LA, Li K, Yang Y, Davis GE, Dellinger MT, Scallan JP
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884898 · Full text
BACKGROUND: Lymphatic malformations are lesions that can be due to inherited or somatic mutations, and they lead to a defective lymphatic vasculature. Activating KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation...
BACKGROUND: Lymphatic malformations are lesions that can be due to inherited or somatic mutations, and they lead to a defective lymphatic vasculature. Activating KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations have been identified recently in patients with lymphatic malformation with lymphedema, chylous ascites, or life-threatening chylothorax. In a lymphatic malformation mouse model, KRAS mutations are associated with a loss of lymphatic valves, which has been proposed to cause chylothorax via retrograde lymph flow into the pleural space. However, the mechanisms underlying the loss of lymphatic valves are unknown. METHODS: To investigate the mechanisms leading to valve loss, we combined the lymphatic-specific and tamoxifen-inducible with () mice and reporter mice to induce the restricted expression of KRAS-G12D and enable valve quantification in postnatal pups. Human dermal lymphatic endothelial cells expressing KRAS-G12D were probed for changes in mRNA and protein expression with quantitative real-time polymerase chain reaction, Western blot, and gel zymography, and mechanistic studies were performed using 3-dimensional cell culture in collagen matrices. RESULTS: Our data showed that lymphatic-specific expression of KRAS-G12D significantly attenuated valve development in the mesentery, diaphragm, and ear skin. Quantitative real-time polymerase chain reaction, Western blot, and gel zymography using human dermal lymphatic endothelial cells expressing KRAS-G12D revealed the upregulation of the PA (plasminogen activator) pathway and MMPs (matrix metalloproteinases). The MMPs were sufficiently activated by plasmin, the product of the PA pathway, in human dermal lymphatic endothelial cells grown in a 3-dimensional collagen matrix, indicating a role for MMPs in the degradation of valve ECM (extracellular matrix) core. Furthermore, a broad-spectrum MMP inhibitor given to mice rescued lymphatic valve development. CONCLUSIONS: We conclude that hyperactive KRAS signaling upregulates MMPs that become excessively activated by the upregulation of the PA pathway. MMPs then degrade the lymphatic valve ECM core, preventing valve formation.
Plasma Proteins Associated With Psychosocial Factors and Heart Disease: The Jackson Heart Study.
O'Brien SN, Gillman MG, Green MD … +20 more , Cruz DE, Floyd JS, Hankinson S, Katz DH, Liu X, Odden MC, Psaty BM, Reiner AP, Rotter JI, Rich SS, Gerszten RE, Shah A, Sims M, Tahir UA, Tinker LF, Wood AC, Yu B, Zannas AS, Raffield LM, Glover LM
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884897 · Full text
BACKGROUND: Knowledge of proteomic mechanisms explaining the link between psychosocial stress and cardiovascular disease is limited. This study aimed to (1) identify plasma proteins associated with psychosocial factors a...
BACKGROUND: Knowledge of proteomic mechanisms explaining the link between psychosocial stress and cardiovascular disease is limited. This study aimed to (1) identify plasma proteins associated with psychosocial factors and (2) assess associational pathways between psychosocial factors, identified proteins, and incident cardiovascular disease events in a discovery cohort, JHS (Jackson Heart Study), and 2 replication cohorts, the CHS (Cardiovascular Health Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: JHS participants from exam 1 (2000-2004) with SomaScan 1.3k platform proteomics data were included (n=2143, mean age=55.3). Depressive symptoms and perceived stress scores were measured via the 20-item Center for Epidemiological Studies scale and an 8-item perceived stress scale adapted for the JHS, respectively. Multivariable linear regression models were used to test the association between psychosocial factors and plasma proteins, controlling for age, sex, proteomics batch, and estimated glomerular filtration rate. Bonferroni correction was used for multiple testing (<3.782×10) and meta-analyses were performed across cohorts. Mediation analyses with Cox proportional hazards models were used to evaluate potential proteomic pathways in the association between psychosocial factors and coronary heart disease, heart failure, and stroke in JHS. RESULTS: Angiopoietin-2 (=0.014, SE=0.003, <0.001), contactin-5 (=-0.017, SE=0.003, <0.001), growth/differentiation factor 15 or macrophage inhibitory cytokine 1 (=0.014, SE=0.002, <0.001), neural cell adhesion molecule 120 (=-0.016, SE=0.003, <0.001), and KYNU (kynureninase; =0.014, SE=0.003, <0.001) were each significantly associated with depressive symptoms, with angiopoietin-2, contactin-5, macrophage inhibitory cytokine 1, and neural cell adhesion molecule 120 replicating in CHS and MESA. Leukotriene A-4 hydrolase was associated with perceived stress (=0.0235, SE=0.005, <0.001). Macrophage inhibitory cytokine 1 partially accounted for the association between depressive symptoms and incident coronary heart disease in JHS (23%; <0.001). CONCLUSIONS: Novel associations between psychosocial factors, plasma proteins, and cardiovascular disease were identified in JHS. Circulating proteomic profiles across 3 cardiovascular disease cohorts showed differences in protein concentrations by psychosocial measures. Future investigations should identify additional potentially targetable proteomic mechanisms by which psychosocial factors contribute to disease.
ABCA1-Mediated Structural Diversity of HDL Subspecies and Their Proposed Roles in Cardioprotection.
Heinecke JW, Segrest JP, Phillips MC … +1 more , Davidson WS
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884896 · Full text
The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of H...
The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by the ABCA1 pathway is relatively well understood. However, additional research is needed to confirm the clinical significance of this pathway. It is also important to determine how, and whether, the antioxidative, immunologic, and anti-inflammatory properties of HDL subspecies, including those containing low-abundance proteins, contribute to cardioprotection.
Macrophage Efferocytosis in Heart.
Inui H, Yu X, Pfrender E … +3 more , Bednarek J, Zhang L, Thorp EB
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884895 · Full text
Efficient clearance of dying cells by efferocytosis is critical for organ development, inflammation resolution, and tissue repair. In the heart, the stakes of efficient clearance are high in that inefficient efferocytosi...
Efficient clearance of dying cells by efferocytosis is critical for organ development, inflammation resolution, and tissue repair. In the heart, the stakes of efficient clearance are high in that inefficient efferocytosis promotes an inflammatory environment that stresses the health of surrounding nonregenerative cardiomyocytes. Herein, we discuss the fundamental protagonists and therapeutic implications of efferocytosis within the myocardium during cardiac development, myocardial regeneration, and myocardial infarction.
Sleep and Risk for Heart Disease and Stroke.
Spaulding EM, Astavans A, Bagga A … +11 more , Zhao H, Wilson G, Antonsdottir I, Kalra D, Ding J, Isakadze N, Khoury SR, Li J, Lucey BP, Lutsey PL, Martin SS
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41884894 · Full text
Getting healthy sleep was recognized in 2022 by the American Heart Association as a key health behavior of Life's Essential 8 based on growing evidence of its impact on cardiovascular health. American Heart Association g...
Getting healthy sleep was recognized in 2022 by the American Heart Association as a key health behavior of Life's Essential 8 based on growing evidence of its impact on cardiovascular health. American Heart Association guidelines recommend that adults aged ≥20 years get on average 7 to 9 hours of sleep per night, based on self-reported measures. However, many adults report getting inadequate sleep duration, a trend expected to worsen through 2050. For these reasons, the relationship between sleep, including its multidimensional components (eg, timing, efficiency, regularity, and architecture), and cardiovascular disease must be evaluated further. In this review, we summarize the current evidence on the association of multidimensional sleep with heart disease and stroke risk. In addition, we discuss the advantages and limitations of various sleep assessments from self-report to direct measurement via novel digital health technologies.
Could ELA Mend a Torn Aorta.
Golledge J, Thanigaimani S
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41853868 · Publisher ↗
Abstract loading — click title to view on PubMed.
RNA Splicing of the Gene Promotes Endothelial Cell Senescence and Atherosclerosis Development.
Ni Q, Qi H, Chu Y … +12 more , Cao R, Wang Y, Yang S, Yao Y, Wang H, Yuan K, Lv L, Ye M, Xue G, Zhang L, Guo X, Li Y
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41853867 · Publisher ↗
BACKGROUND: Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of...
BACKGROUND: Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of ECs. Recent studies have revealed that cell phenotype-specific alternative splicing of FGFR2 premRNA (precursor mRNA) results in the mutually exclusive inclusion of either exon IIIb or IIIc, leading to critical differences in receptor function. This study aimed to investigate the role of FGFR2 alternative splicing in EC senescence and atherosclerosis development, and to elucidate the underlying mechanisms. METHODS: Clinical samples and animal models were used to assess the association between FGFR2-IIIc isoform expression and EC senescence as well as atherosclerotic plaque formation. The mechanisms underlying FGFR2-IIIc-induced EC senescence were elucidated through a combination of in vivo and in vitro investigations. In addition, genetically engineered mice with endothelial-specific overexpression or knockdown of FGFR2-IIIc were utilized to investigate the impact of FGFR2-IIIc on vascular endothelial senescence and the progression of atherosclerosis. RESULTS: Elevated expression of the FGFR2-IIIc isoform was detected in clinical samples and animal models of aging and atherosclerosis, where it correlated with both EC senescence and atherosclerotic plaque formation. Mechanistically, the alternative splicing-mediated switch from FGFR2-IIIb to FGFR2-IIIc established an FGF2-FGFR2-IIIc autocrine feedback loop, which drove ECs toward a senescence-associated secretory phenotype via the PKC (protein kinase C) ε/STAT3 (signal transducer and activator of transcription) pathway. Senescence-inducing stimuli promoted the binding of the splicing factor hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) to exon IIIb of the gene, leading to skipping of this exon. Notably, EC-specific knockout of FGFR2-IIIc in mice reduced plaque area, suppressed senescence-associated secretory phenotype gene expression, and attenuated cellular senescence compared with controls. CONCLUSIONS: This study reveals that FGFR2 splicing mediated by hnRNP H1 promotes EC senescence and atherosclerosis via an FGF2-FGFR2-IIIc autocrine loop. These findings identify FGFR2-IIIc as a potential therapeutic target for age-related atherosclerosis.
Hypertriglyceridemia Does Not Worsen Thoracic Aortic Aneurysm and Dissection in GPIHBP1 Knockout Mice-Brief Report.
Wang B, Meng Z, Li J … +4 more , Wu F, Song B, Huang W, Liao J
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41853866 · Publisher ↗
BACKGROUND: Hypertriglyceridemia is an established risk factor for atherosclerotic cardiovascular disease and has recently been implicated in abdominal aortic aneurysm pathogenesis. However, its role in thoracic aortic a...
BACKGROUND: Hypertriglyceridemia is an established risk factor for atherosclerotic cardiovascular disease and has recently been implicated in abdominal aortic aneurysm pathogenesis. However, its role in thoracic aortic aneurysm and dissection (TAAD) remains undefined. METHODS: We investigated the impact of hypertriglyceridemia on experimental TAAD using GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1) knockout mice as a hypertriglyceridemia model. TAAD was induced in 3- to 4-week-old mice via oral β-aminopropionitrile administration for 28 days. RESULTS: Despite progressive hypertriglyceridemia in GPIHBP1 knockout mice during β-aminopropionitrile treatment, no significant differences in TAAD incidence, mortality, or the ratio of affected aortic segments to aortic full length were observed between GPIHBP1 knockout mice and their wild-type littermates. Histopathologic and molecular analyses revealed comparable elastin fragmentation, ECM (extracellular matrix) degradation, vascular smooth muscle cell phenotypic transition, and inflammatory cell infiltration in thoracic aortas of both genotypes. These results remained consistent across sexes and different β-aminopropionitrile dosing regimens. CONCLUSIONS: Our findings demonstrate that hypertriglyceridemia does not significantly exacerbate the development or progression of β-aminopropionitrile-induced TAAD in GPIHBP1-deficient mice.
Exercise Attenuates Aortic Dissection Via PDE5A-Mediated Inhibition of Vascular Smooth Muscle Cell Phenotypic Switch.
Zhang Y, Wu C, Du D … +9 more , Hu J, Li Z, Wang Y, Li B, Mu J, Chen X, Yu Y, Wu N, Zuo S
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41853865 · Full text
BACKGROUND: Aortic dissection (AD) is a life-threatening condition and involves pathological vascular smooth muscle cell (VSMC) phenotypic switching from a contractile to a synthetic state. Although exercise confers broa...
BACKGROUND: Aortic dissection (AD) is a life-threatening condition and involves pathological vascular smooth muscle cell (VSMC) phenotypic switching from a contractile to a synthetic state. Although exercise confers broad cardiovascular benefits, its role in AD pathogenesis remains unclear. This study aimed to determine whether exercise attenuates AD by modulating VSMC phenotype and to elucidate the underlying molecular mechanism. METHODS: Human aortic tissues from AD patients were analyzed for VSMC phenotypic markers and PDE5A (phosphodiesterase 5A) expression. A β-aminopropionitrile induced AD model was established in wild-type mice with or without treadmill exercise intervention. RNA sequencing, gain- and loss-of-function experiments, and mechanistic assays were employed to investigate the roles of PDE5A and its transcriptional regulator RUNX1 (runt-related transcription factor 1). RESULTS: In human AD lesional tissues, contractile VSMC markers (MYH11 [myosin heavy chain 11], CNN1 [calponin 1], and α-SMA [alpha-smooth muscle actin]) were significantly downregulated, whereas the synthetic marker osteopontin was upregulated. In β-aminopropionitrile-induced AD mice, exercise improved survival, reduced aortic dilation and AD incidence, and preserved the contractile VSMC phenotype. RNA-seq analysis identified PDE5A as a key exercise-responsive gene. PDE5A expression was reduced in human AD lesional tissues and β-aminopropionitrile-treated mice but was upregulated by exercise. VSMC-specific overexpression of PDE5A attenuated AD progression, whereas PDE5A inhibition abolished the attenuating effects of exercise. We further identified RUNX1 as a transcriptional repressor of PDE5A that is upregulated in AD conditions and suppressed by exercise. Inhibition of RUNX1 upregulated PDE5A expression, preserved VSMC contractility, and reduced AD incidence. CONCLUSIONS: In conclusion, we identify a novel RUNX1-PDE5A axis that mediates the beneficial effects of exercise against AD. Exercise attenuates AD by reducing RUNX1-mediated transcriptional repression of PDE5A, thereby maintaining VSMC contractile phenotype. These findings highlight the RUNX1-PDE5A pathway as a promising preventive target.
Targeting Endothelial PDK4-EndoMT Feedback Loop Mitigates the Development of Thoracic Aortic Dissection in Mice.
Cao X, Guo X, Huang H … +11 more , Shen H, Zhu J, Gao Y, Liu A, Wang T, Xue Z, Tang C, Ye L, Shao L, Yu Y, Shen Z
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41853864 · Full text
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of en...
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening acute vascular condition with high morbidity and mortality. Endothelial cells (ECs) are critical for maintaining vascular homeostasis, yet the role of endothelial-to-mesenchymal transition (EndoMT), a key cell-fate process in vascular development and disease, in TAD remains poorly defined. Furthermore, the functional role of PDK4 (pyruvate dehydrogenase kinase 4) as a driver of this pathological cell-fate transition has not been elucidated. METHODS: To delineate the mechanistic contribution of EndoMT to TAD, we integrated transcriptomic profiling and immunofluorescence analysis in human aortic specimens and a β-aminopropionitrile-induced murine model. Following the identification of PDK4 as a critical downstream effector of EndoMT signaling via RNA-sequencing and chromatin immunoprecipitation assays, its functional role was validated using conditional EC-specific knockout mice and adeno-associated virus-mediated endothelial gene modulation. Serum samples were collected, and ELISA was used to measure levels of endothelial injury markers for assessing EC-dysfunction. In addition, therapeutic potential was assessed using dichloroacetate, a small-molecule PDK4 inhibitor. RESULTS: A robust activation of the EndoMT gene program was observed in both human TAD specimens and murine aortic tissues, characterized by the loss of endothelial identity and acquisition of mesenchymal traits. Transcriptomic screening pinpointed PDK4 as a critical mediator upregulated during EndoMT. Mechanistically, we demonstrated that the transcription factor directly binds to the promoter to activate its expression. In turn, excessive PDK4 promotes EndoMT via lactate accumulation, establishing a PDK4-EndoMT positive feedback loop that sustains pathological remodeling in TAD. In vivo, EC-specific overexpression induced spontaneous aortic dissection and rupture. Conversely, EC--knockdown or pharmacological inhibition with dichloroacetate attenuated TAD progression, preserved vascular integrity, and improved survival. CONCLUSIONS: Our findings demonstrate that the pathological EndoMT program is activated in ECs by PDK4, which aggravates TAD development in β-aminopropionitrile-induced mouse models, highlighting PDK4 as a promising therapeutic target for TAD.
Dynamic Behavior of Carotid Arteries Determined by Black-Blood Cine MR Imaging: Potential Plaque Vulnerability Indicators.
Qiao H, Yang Q, Xu N … +9 more , Liu J, Huo R, Yu S, Wang Q, Zhu L, Wang S, Cao J, Wang T, Zhao X
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41815087 · Publisher ↗
BACKGROUND: Plaque rupture is influenced by both plaque components and the dynamic behavior of the arterial wall. This study aimed to characterize dynamic changes in carotid lumen and wall using magnetic resonance black...
BACKGROUND: Plaque rupture is influenced by both plaque components and the dynamic behavior of the arterial wall. This study aimed to characterize dynamic changes in carotid lumen and wall using magnetic resonance black blood cine imaging and to determine their value in discriminating plaque vulnerability. METHODS: Patients with symptomatic carotid atherosclerotic stenosis scheduled for carotid endarterectomy were recruited and underwent black blood cine imaging. Histological slices were used to identify intraplaque hemorrhage, lipid-rich necrotic core, calcification, loose matrix, and fibrous cap rupture, and were matched with magnetic resonance images. Dynamic changes in lumen area, wall area, normalized wall index (NWI), and maximum wall thickness were calculated, while static measurements were derived by averaging these parameters over cardiac phases. These measurements were compared using independent test or Mann-Whitney test, depending on data normality. Logistic regression and receiver operating characteristic analyses were conducted to discriminate fibrous cap rupture and to distinguish symptomatic status. RESULTS: Eighty magnetic resonance cine slices from 29 patients (mean age, 64.9±7.6 years; 22 males) were matched with histology. Slices with intraplaque hemorrhage (=0.019) or lipid-rich necrotic core (=0.016) exhibited lower NWI changes. Maximum wall thickness changes were higher in slices with loose matric (=0.032) but reduced in slices with calcification (=0.036). Maximum wall thickness changes were protective against fibrous cap rupture (odds ratio, 0.871; =0.008; area under the receiver operating characteristic curve, 0.765). Symptomatic arteries showed lower maximum wall thickness, wall area, and NWI changes, but higher lumen area changes (<0.05). Static lumen area and NWI were significantly altered in slices with intraplaque hemorrhage, lipid-rich necrotic core, or loose matrix (<0.05), but static measurements showed no significant association with fibrous cap rupture. In discriminating symptomatic from asymptomatic arteries, combining NWI and lumen area changes achieved an area under the receiver operating characteristic curve of 0.946, whereas static NWI reached an area under the receiver operating characteristic curve of 0.971. CONCLUSIONS: Dynamic changes assessed by magnetic resonance black blood cine imaging are associated with plaque components, fibrous cap rupture, and symptomatic status, suggesting their potential as quantitative markers of plaque vulnerability.
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