Arteriosclerosis, Thrombosis, And Vascular Biology[JOURNAL]
Sun
200 papers
Association of Coronary Vasculitis Sequelae With Atherosclerosis in Adults With a History of Kawasaki Disease: Autopsy Pathological Findings.
Yokouchi Y, Asakawa N, Sato W … +5 more , Asakura K, Hayashi K, Nakamura Y, Ae R, Takahashi K
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41503696 · Publisher ↗
BACKGROUND: In Kawasaki disease (KD), coronary arteritis occurring in infancy can lead to long-term sequelae, such as luminal dilatation, stenosis, intimal thickening, and calcification. However, the long-term evolution...
BACKGROUND: In Kawasaki disease (KD), coronary arteritis occurring in infancy can lead to long-term sequelae, such as luminal dilatation, stenosis, intimal thickening, and calcification. However, the long-term evolution of these lesions, particularly the effect of superimposed atherosclerosis in adulthood, remains poorly understood. This study aimed to investigate coronary artery lesions in adults with a history of KD and clarify the relationship between sequelae of vasculitis and atherosclerosis. METHODS: We analyzed 7 autopsy cases of sudden cardiac death in adults with a confirmed history of KD and documented coronary artery aneurysms. Clinical data, including acute-phase treatment history, body mass index, heart weight, coronary risk factors, and detailed coronary histopathology, were evaluated. RESULTS: All aneurysms were located at the coronary ostia and showed marked intimal thickening with severe calcification, leading to luminal narrowing. Thrombotic occlusion within the aneurysm was identified in 1 case. In 3 patients aged older than 30 years, atherosclerotic changes were observed in the thickened intima of persistent aneurysmal segments or dilated portions. One patient with a regressed aneurysm died of acute myocardial infarction caused by plaque rupture. Sequelae of vasculitis were widely distributed in nonaneurysmal coronary branches, and atherosclerotic changes were also noted in these regions. CONCLUSIONS: In adults with persistent coronary aneurysms due to KD, atherosclerotic lesions may develop not only in aneurysmal segments but also in nondilated arteries with scarring due to vasculitis. Individuals with prior KD and coronary aneurysms may require long-term management for thrombotic risk and the prevention of atherosclerosis, beginning in early adulthood.
Clinical and Molecular Differences of Hypertensive Disorders During Pregnancy.
Horii M, Morey R, Chousal JN … +11 more , Edlabadkar A, Hakim A, Liu TN, Meads M, Stanley V, La Belle S, Adkins S, Lamale-Smith L, Wolf RB, Aisagbonhi O, Jacobs MB
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41467353 · Full text
BACKGROUND: Hypertensive disorders of pregnancy (HDP) comprise a spectrum of 4 subtypes: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia (PE), and superimposed preeclampsia (siPE). Although oft...
BACKGROUND: Hypertensive disorders of pregnancy (HDP) comprise a spectrum of 4 subtypes: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia (PE), and superimposed preeclampsia (siPE). Although often characterized as a spectrum of disease severity, there have been limited comparative studies of detailed clinical and molecular characteristics of these disorders. We hereby evaluate HDP subtypes using clinical, placental histopathologic, and molecular data to compare similarities and differences between HDP subtypes. METHODS: We used data from an over 10-year-long pregnancy cohort with detailed clinical and placental pathology, as well as placental tissue RNA-sequencing, to compare findings between HDP subtypes using a nested case-control design. Clinical diagnosis was based on current ACOG criteria, and placental gross and histological examination was based on the Amsterdam consensus statement. RESULTS: Clinical data analysis showed cHTN and gHTN to be more likely to have normal placental pathology, while PE and siPE were more enriched in maternal vascular malperfusion. RNA-seq showed distinct gene expression signatures and pathway activation across HDP subgroups. We could not identify any molecular evidence that preeclampsia (PE or siPE) was an advanced stage of hypertensive disorder (gHTN or cHTN), but rather identified distinct gene expression profiles between these entities, suggesting preeclampsia (PE or siPE) and hypertension (gHTN or cHTN) are distinct pathophysiological conditions. Finally, we found that, in the presence of maternal vascular malperfusion, PE and siPE share significant gene expression profiles and pathway activation. CONCLUSIONS: Our findings suggest that maternal vascular malperfusion specifically differentiates pregnancies that progress to PE and siPE. Maternal vascular malperfusion is thought to initiate in early gestation, indicating the cascade to PE/siPE may be differentiated from gHTN/cHTN early in pregnancy. Incorporating placental histopathologic evaluation is an essential future avenue in probing the etiology of HDP.
NAT10-Mediated ac4C-Modification Exacerbates Ferroptosis by Stabilizing HMOX1 in Deep Vein Thrombosis.
Zhang Y, Zhang Z, Liu X … +13 more , Chu C, Yu X, Han Q, Li W, Zhang T, Zu H, Fan N, Wei R, Shi F, Li F, Xu F, Wang B, Li X
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41467352 · Full text
BACKGROUND: Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated th...
BACKGROUND: Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated that NAT10 (-acetyltransferase 10)-mediated 4-acetylcytidine modification exerts unique roles in ferroptosis, but its roles are still elusive in DVT. METHODS: To explore the potential mechanism of NAT10 and ferroptosis on thrombogenesis, we used NAT10 and GPX4 (glutathione peroxidase 4) knockout mice as an in vivo model, and utilized techniques, such as RNA immunoprecipitation, acRIP-qPCR (acetylated RNA immunoprecipitation-quantitative PCR), 4-acetylcytidine Dot Blotting assay, and Western blotting, for detailed molecular analysis. RESULTS: GPX4 is a pivotal gene that suppresses ferroptosis. Utilizing endothelial cell-specific GPX4 conditional knockout mice (GPX4Cdh5-Cre), we proved that ferroptosis in endothelial cells promotes the formation of thrombosis. Previous evidence indicates that NAT10 overexpression induces ferroptosis and downregulates GPX4 expression. Here, we found that NAT10 expression was elevated in DVT mice, and silencing of NAT10 markedly attenuated ferroptosis both in vitro and in vivo. Furthermore, endothelial cell-specific knockout of NAT10 (NAT10Cdh5-Cre) demonstrated a reduction in endothelial ferroptosis, thereby inhibiting both the formation and progression of DVT. Mechanistic studies indicated that NAT10 facilitated the N4-acetylcytidine modification of HMOX1 (heme oxygenase 1), which enhanced its mRNA stability, leading to the accumulation of ferrous ions, and exacerbating endothelial dysfunction in DVT. CONCLUSIONS: Collectively, our data elucidate that downregulation of NAT10 mitigates endothelial ferroptosis and prevents DVT formation and progression by modulating HMOX1 expression, which offers a potential novel strategy for the prevention and treatment of thrombosis in DVT.
Nonhematopoietic MicroRNA-26b Augments Atherosclerosis Development by Increasing Endothelial Inflammation and Leukocyte Adhesion-Brief Report.
Peters LJF, Bidzhekov K, Megens RTA … +10 more , Jansen Y, Jin H, Jans A, Lin C, Haberbosch M, Bartneck M, Biessen EAL, Weber C, Döring Y, van der Vorst EPC
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41467351 · Full text
BACKGROUND: Atherosclerosis is a leading cause of cardiovascular diseases, and microRNA-26b (miR-26b) has emerged as a significant regulator in its development. This study investigates the role of nonhematopoietic miR-26...
BACKGROUND: Atherosclerosis is a leading cause of cardiovascular diseases, and microRNA-26b (miR-26b) has emerged as a significant regulator in its development. This study investigates the role of nonhematopoietic miR-26b in atherosclerosis. METHODS: To study the specific role of nonhematopoietic cell miR-26b in atherosclerosis development, we used a reverse bone marrow transplantation model combined with 12-week Western-type diet feeding. RESULTS: Nonhematopoietic-specific miR-26b deficiency exacerbated atherosclerosis, characterized by larger plaques with increased collagen and necrotic core content. Enhanced VCAM-1 (vascular cell adhesion molecule 1) expression correlated with elevated leukocyte adhesion in ex vivo perfusion studies. Restoration of miR-26b levels in human coronary artery endothelial cells reduced inflammatory responses and leukocyte adhesion. CONCLUSIONS: Our findings highlight that nonhematopoietic miR-26b plays a protective role in atherosclerosis by modulating endothelial cell function, suggesting potential therapeutic applications for miR-26b mimics in cardiovascular disease management.
Mechanisms Linking Insomnia and Cardiometabolic Disease Risk.
Fernandez-Mendoza J
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41467350 · Full text
About 10% to 15% of the adult population reports frequent, chronic insomnia symptoms of difficulty initiating or maintaining sleep associated with daytime impairment (ie, insomnia disorder). An additional 30% to 40% repo...
About 10% to 15% of the adult population reports frequent, chronic insomnia symptoms of difficulty initiating or maintaining sleep associated with daytime impairment (ie, insomnia disorder). An additional 30% to 40% report insomnia symptoms at any given time. Not only is insomnia disproportionally more prevalent in individuals with cardiometabolic diseases, but evidence also demonstrates that insomnia, particularly when coupled with objective short sleep duration, increases the risk of developing cardiometabolic diseases. Insomnia is a disorder of 24-hour hyperarousal, a multidimensional construct ranging from cognitive to physiological dysregulation. Physiological hyperarousal in insomnia occurs in the form of hyperactivation of wake-promoting and emotion-regulating areas (eg, glucose metabolism in the ascending reticular activating system), hypothalamic-pituitary-adrenal axis (eg, cortisol levels), sympatho-adrenomedullary axis (eg, norepinephrine levels), cardiac sympathetic-parasympathetic system (eg, heart rate variability), and low-grade inflammation (eg, cytokine levels). Physiological hyperarousal in insomnia inhibits sleep ability, leading to objective short sleep, and increases cardiometabolic disease risk. This brief review summarizes the evidence on the pathophysiologic mechanisms associating insomnia with cardiometabolic disease risk, including current knowledge on the phenotypic heterogeneity of insomnia based on objective sleep duration. Future studies need to test the molecular, cellular, and behavioral mechanisms at play in increasing cardiometabolic disease risk across robustly identified insomnia phenotypes.
Endothelial Cell Regulation of Lipid Uptake During Feeding and Fasting.
Goldberg IJ, Tirumalasetty M, Peche VS … +5 more , Gaballa R, Cabodevilla AG, Komack M, Miao QR, Abumrad NA
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41431926 · Full text
Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bin...
Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36 (cluster of differentiation 36). The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health.
Lipid-Related Polygenic Risk Score and Its Association With Plaque Rupture Versus Erosion.
Hamana T, Gaynor BJ, Grogan A … +13 more , Turoni-Glitz A, Kawakami R, Shiraki T, Sekimoto T, Tanaka T, Fujiyoshi K, Nakayama T, Adachi Y, Williams D, Diaz KM, Mitchell BD, Virmani R, Finn AV
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41431925 · Publisher ↗
BACKGROUND: Distinct plaque morphologies underlie the major causes of acute coronary syndrome and sudden cardiac death. We used polygenic risk scores (PRSs) for hypercholesterolemia and hypertriglyceridemia, 2 major risk...
BACKGROUND: Distinct plaque morphologies underlie the major causes of acute coronary syndrome and sudden cardiac death. We used polygenic risk scores (PRSs) for hypercholesterolemia and hypertriglyceridemia, 2 major risk factors for coronary artery disease (CAD), to evaluate the relative contributions of these risk factors to specific plaque morphologies, specifically plaque rupture and erosion. METHODS: DNA was extracted from formalin-fixed paraffin-embedded tissues and genotyped for 954 subjects from our sudden death autopsy registry, with cause of death determined by autopsy. LDL (low-density lipoprotein)-specific and triglyceride-specific PRSs were constructed based on the Global Lipids Genetics Consortium genome-wide association study results, excluding variants associated with both traits (<0.05). RESULTS: Subjects in the highest LDL-specific PRS quintile had significantly more plaque rupture, ≥75% lumen narrowing, thrombotic CAD, and CAD-related death compared with those in the lowest quintile. After adjusting for the first 10 principle components, LDL-specific PRS remained significantly associated with rupture (odds ratio [OR], 1.22 per SD [95% CI, 1.04-1.43]; =0.017), ≥75% lumen narrowing (OR, 1.33 [95% CI, 1.13-1.57]; <0.001), thrombotic CAD (OR, 1.21 [95% CI, 1.04-1.41]; =0.016), and CAD-related death (OR, 1.31 [95% CI, 1.13-1.52]; <0.001). In contrast, triglyceride-specific PRS was significantly associated with thrombotic CAD (OR, 1.20 [95% CI, 1.03-1.40]; =0.020) and showed a trend toward association with plaque rupture (OR, 1.15 [95% CI, 0.98-1.35]; =0.091). No association was observed between LDL-/triglyceride-specific PRS and plaque erosion. CONCLUSIONS: This is the first study to associate lipid PRSs with specific plaque morphologies, revealing distinct pathogenic mechanisms underlying plaque rupture and erosion. Early genetic risk stratification and subsequent lipid-lowering interventions may provide substantial clinical benefits in mitigating cardiovascular risk, particularly in relation to plaque rupture. Our findings raise questions about the effectiveness of such strategies in preventing plaque erosion, suggesting the need for further investigation into its underlying pathogenesis.
Progression of Established Atherosclerotic Lesions Is Not Inhibited by Endothelial Knockout of Caveolin-1-Brief Report.
Muñiz-Anquela R, Redondo-Angulo I, Lewis EA … +6 more , Lolo FN, González-Cintado L, Toledano-Donado M, Pulgarín-Alfaro M, Del Pozo MA, Bentzon JF
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41431924 · Full text
BACKGROUND: Eradicating endothelial caveolae by deleting the (caveolin-1) gene reduces LDL (low-density lipoprotein) uptake in arteries and efficiently prevents early atherogenesis, but the role in established atheroscl...
BACKGROUND: Eradicating endothelial caveolae by deleting the (caveolin-1) gene reduces LDL (low-density lipoprotein) uptake in arteries and efficiently prevents early atherogenesis, but the role in established atherosclerosis is unknown. Here, to examine CAV1 as a potential therapeutic target, we deleted endothelial in mice after lesion development and analyzed the effect on LDL uptake and lesion progression. METHODS: To allow timed endothelium-specific deletion, we generated male and female mice with floxed alleles and endothelium-specific inducible Cre recombinase. Atherosclerosis was induced by virus-mediated PCSK9 (proprotein convertase subtilisin/kexin type 9) gene transfer and a high-cholesterol diet. After 16 weeks of lesion development, endothelial deletion was induced by a series of tamoxifen injections, repeated after 4 weeks, and the mice were followed for another 4 weeks. Mice were injected with fluorescently labeled LDL at 1 and 18 hours before euthanasia to study uptake and retention in lesions. Sections of the aortic root were analyzed for lesion size, composition, and LDL accumulation. RESULTS: Efficient conditional knockout of endothelial was confirmed by CAV1 immunostaining and by the loss of caveolae by electron microscopy. Loss of endothelial for 8 weeks reduced LDL entry into lesions but did not significantly decrease LDL retention, lesion lipid accumulation, fibrous tissue, or lesion size. In males, a reduction in macrophages was seen. CONCLUSIONS: Targeting CAV1 does not efficiently block LDL entry or reduce lesion progression in established atherosclerosis. These findings open several questions for further research, including alternative LDL entry mechanisms that could circumvent caveolar transport in established atherosclerosis.
Cytosolic Versus Lysosomal Lipolysis in Adipose Tissue: Opposing Roles in Cardiometabolic Disease.
Yeh YS, Huang J, Liu Z … +3 more , Cosme C, Zhang X, Razani B
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41431923 · Full text
Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonic...
Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by ATGL/PNPLA2 (adipose triglyceride lipase) and the lysosomal pathway governed by LAL/LIPA (lysosomal acid lipase). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.
Therapeutic Potential of C1-Inhibitor in Vascular Diseases and Beyond.
Sundler Björkman L, Eswaran H, Grover SP
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410053 · Full text
C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally devel...
C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease 2019.
Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
Perkins MV, Mackman N
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410052 · Full text
Viral hemorrhagic fever (VHF) describes different diseases caused by several viruses from 6 virus families: , , , , , and . VHF was once considered a geographically localized problem, but due to expanding vector ranges a...
Viral hemorrhagic fever (VHF) describes different diseases caused by several viruses from 6 virus families: , , , , , and . VHF was once considered a geographically localized problem, but due to expanding vector ranges and increased human contact with animal reservoirs and hosts, the number of VHF cases is increasing. As the name indicates, VHF is associated with bleeding. Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to dysregulation of the hemostatic system. Many studies have measured different parameters and various biomarkers in samples from infected humans and nonhuman primate models. For example, Ebola virus infection in a nonhuman primate model leads to increased TF (tissue factor) expression in peripheral blood mononuclear cells and extracellular vesicles. In dengue virus infection, thrombocytopenia and platelet dysfunction occur. There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses. Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability. While a significant body of work exists examining different aspects of the various viral infections that may lead to bleeding, there are still many open questions and areas for investigation. Therefore, more studies are needed to better understand the mechanisms underlying bleeding in VHF caused by different viruses.
Immune Cell Regulation of Zebrafish Heart Regeneration.
Zhang S, Sassu E, Marín-Juez R
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410051 · Publisher ↗
Zebrafish possess a remarkable capacity to regenerate cardiac tissues after injury, offering a powerful model to dissect the cellular and molecular mechanisms driving heart regeneration. Immune cells play distinct and co...
Zebrafish possess a remarkable capacity to regenerate cardiac tissues after injury, offering a powerful model to dissect the cellular and molecular mechanisms driving heart regeneration. Immune cells play distinct and context-dependent roles during regeneration, from debris clearance and inflammation resolution to modulation of cell proliferation and fibrosis. Here, we review the distinct contributions of neutrophils, macrophages, and lymphoid cells during zebrafish heart regeneration, with a focus on their temporal coordination and regulatory signaling pathways. Understanding proregenerative immune-mediated mechanisms may identify therapeutic targets to enhance cardiac repair in disease contexts, such as myocardial infarction and heart failure.
More Than a Cleanup Crew: The Expanding Biology of Efferocytosis.
Pandit R, Hillman H, Williams JW … +1 more , Yurdagul A
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410050 · Full text
Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recog...
Efferocytosis, the process by which phagocytes clear apoptotic cells, is essential for tissue homeostasis, inflammation resolution, and repair. Once considered a passive waste-disposal process, efferocytosis is now recognized as a dynamic, immunometabolic program that integrates apoptotic cell clearance with metabolic reprogramming and inflammation resolution. In cardiovascular contexts, efficient efferocytosis limits necrosis, enhances the deposition of wound healing matrix proteins, and promotes tissue healing, whereas impaired clearance drives chronic inflammation and maladaptive tissue remodeling. We review the molecular mechanisms governing efferocytosis, including the interplay of find-me, eat-me, and don't-eat-me signals with receptor-mediated cytoskeletal remodeling and lysosomal degradation. We highlight how efferocytosis drives lipid efflux, fatty acid oxidation, amino acid catabolism, and nucleotide recycling, processes that sustain continual efferocytosis and resolution programming. Defects in these pathways, amplified by proteolytic cleavage of apoptotic cell receptors, dysregulated metabolism, and inflammatory mediators, underlie impaired efferocytosis in atherosclerosis, myocardial infarction, vascular aging, and metabolic diseases. Finally, we discuss emerging concepts, including nonprofessional phagocyte contributions, crosstalk with adaptive immunity, and therapeutic strategies to enhance efferocytosis or preserve receptor integrity. Collectively, these insights redefine efferocytosis as more than a cleanup mechanism, positioning it as a central contributor to attenuating cardiometabolic diseases.
Sotagliflozin Enhances Left Ventricular Function and Myocardial Perfusion in Chronic Myocardial Ischemia Through Metabolic and Redox Remodeling.
Muir KC, Stone C, Reddy R … +5 more , Kanuparthy M, Hamze J, Harris DD, Abid MR, Sellke FW
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410049 · Full text
BACKGROUND: Ischemic heart disease is the leading cause of mortality and human suffering globally. It often leaves patients with residual symptomatic burden despite current optimized procedural and medical options. Sotag...
BACKGROUND: Ischemic heart disease is the leading cause of mortality and human suffering globally. It often leaves patients with residual symptomatic burden despite current optimized procedural and medical options. Sotagliflozin, a dual SGLT1/2 (sodium-glucose cotransporter 1 and 2) inhibitor, has emerged for its clinically evident ischemic cardiovascular benefits. We hypothesize that sotagliflozin treatment exerts direct myocardial benefits in ischemic heart disease, independent of comorbid conditions. METHODS: Yorkshire swine (n=22) underwent placement of an ameroid constrictor around the left circumflex coronary artery. Following a 2-week period in which the ameroid gradually closes, swine (n=18) were randomized to receive either 400 mg daily sotagliflozin (n=8) or no drug (n=10) for 5 weeks. Afterwards, swine underwent terminal harvest to acquire cardiac functional data with pressure-volume loops, myocardial perfusion by microsphere injection, and ventricular sectioning. To investigate the cellular and tissue-level impact of therapy, histology, immunoblotting, and high-throughput techniques were performed. RESULTS: Sotagliflozin swine had improved ejection fraction, cardiac output, and stroke work compared with no drug (<0.05) and a reduction in tau (=0.04). Absolute blood flow to the ischemic myocardium was increased in the sotagliflozin group (=0.03). Sotagliflozin swine had a reduction in 3-nitrotyrosine and trichrome staining, representing decreased reactive nitrogen species and myocardial fibrosis (=0.03 for both). Molecularly, sotagliflozin swine demonstrated increased expression of endothelial nitric oxide synthase and superoxide dismutase 3 (=0.02, =0.04; respectively), with upregulated arginine metabolism, protein kinase A/cyclic adenosine monophosphate signaling, as well as glycolysis, fatty acid oxidation, and citric acid cycle. CONCLUSIONS: Sotagliflozin treatment improved left ventricular function, myocardial perfusion, and diastolic relaxation, likely through reduced nitrosative stress and myocardial fibrosis, improved nitric oxide coupling, enhanced insulin signaling, and favorable metabolic shifts. This study suggests a potential role for sotagliflozin as a cardioprotective therapy in patients with ischemic heart disease beyond current treatment strategies.
Cardiovascular Manifestations and Immunobiology of Sarcoidosis.
Weintraub NL, Guha A, Taskar V … +5 more , Elam RE, Chiang AWT, Ley K, Sharma G, Hedrick CC
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41410048 · Full text
Sarcoidosis is a chronic inflammatory disease of unknown cause that can affect the heart and blood vessels, causing cardiomyopathy, pulmonary hypertension, and vasculitis. The pathological hallmark of sarcoidosis is the...
Sarcoidosis is a chronic inflammatory disease of unknown cause that can affect the heart and blood vessels, causing cardiomyopathy, pulmonary hypertension, and vasculitis. The pathological hallmark of sarcoidosis is the formation of noncaseating granulomas consisting of monocytes and dendritic cells, macrophages, multinucleated giant cells, and T cells. Sarcoidosis has features of autoimmune disease, and many candidate self-epitopes have been identified, but experimental validation is lacking. There is a strong hereditary component associated with the human leukocyte antigen region on chromosome 6. Symptoms of the disease may be subtle and often go unrecognized by patients and practitioners. Catastrophic events, including sudden cardiac death caused by lethal arrhythmias, can be the initial manifestation of the disease. Diagnosis is challenging and limited by the lack of sensitive and specific diagnostic tools, which also hampers monitoring of disease activity. Here, we discuss the cardiovascular manifestations and underlying immunobiology of sarcoidosis. We also review current diagnostic and treatment approaches for cardiac sarcoidosis, as well as the challenges faced by patients and clinicians and opportunities for future research.
Vascular Toxicities of Cancer Therapies: 2025 Update.
Donisan T, Balanescu DV, Abe JI … +3 more , Lerman A, Iliescu CA, Herrmann J
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41376595 · Full text
Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but have been linked to adverse, including cardiovascular, events. Vascular toxicities associated with cancer treatme...
Advances in cancer therapies have transformed many malignancies into chronic or manageable conditions, but have been linked to adverse, including cardiovascular, events. Vascular toxicities associated with cancer treatment range from abnormal vasoreactivity to accelerated atherosclerosis, arterial thrombotic events, vasculitis, and arterial aneurysms or dissections. 5-fluorouracil and VEGF (vascular endothelial growth factor) inhibitors are the agents most commonly linked to abnormal vasoreactivity, whereas BCR-ABL (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog) inhibitors and immune checkpoint inhibitors have been associated with accelerated atherosclerosis. Arterial thrombotic events are seen with VEGF and BCR-ABL inhibitors as well as platinum drugs. Vasculitis emerged with the use of immune checkpoint inhibitors, and arterial aneurysms and dissections with VEGF inhibitors. Radiation therapy can lead to several of the outlined vascular toxicities. This review comprehensively explores the mechanisms of vascular complications associated with chemotherapy, targeted therapies, immunotherapies, and radiation therapy. Key contributors include endothelial injury and dysfunction, oxidative stress, and inflammation. An understanding of the mechanisms of vascular toxicities may facilitate optimal treatment and preventive strategies in patients with cancer.
Persistence of Vascular Calcification: A Failure of Cell-Mediated Resorption.
Wang XH, Dabeer S, Huang Y … +2 more , Weitzmann MN, O'Neill WC
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41376594 · Publisher ↗
BACKGROUND: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinical...
BACKGROUND: Medial arterial calcification is a common lesion associated with aging, chronic kidney disease, and diabetes that can lead to poor outcomes. Because the calcification is extensive when first apparent clinically or even radiologically, optimal therapy should target reversal in addition to prevention. However, studies to date suggest that medial calcification is irreversible under physiological conditions. This lack of reversal was investigated further by implanting calcified human arteries or hydroxyapatite subcutaneously into mice, or culturing them with murine osteoclasts in vitro. METHODS: Calcified human tibial arteries, obtained from amputations and previously frozen, were implanted subcutaneously in the dorsum of mice. Mineral content was measured by microcomputed tomography before and after implantation and compared with the calcium content of implanted pure hydroxyapatite or murine bone particles, along with histology. Calcified arteries were also incubated in vitro with osteoclasts generated by treating murine macrophages with receptor activator of NF-κB (nuclear factor kappa B). RESULTS: There was no decrease in mineral content of implanted arteries over 6 weeks and only minimal loss of calcium in devitalized bone particles, compared with almost complete resorption of hydroxyapatite. No resorption of hydroxyapatite occurred when implanted within a cell-impermeable diffusion chamber. Multinucleated giant cells, negative for osteoclast markers, were numerous among implanted hydroxyapatite, but rare in implanted arteries and bone. There was no histological evidence of resorption in calcified arteries incubated with osteoclasts. CONCLUSIONS: Hydroxyapatite is readily reabsorbed in vivo by a cell-mediated process not involving osteoclasts. The lack of resorption of medial arterial calcifications, even in the presence of osteoclasts, indicates that calcifications have properties that prevent cell-mediated resorption. Further studies are needed to identify these properties and develop strategies to overcome this.
Gestational Glucocorticoids' Exposure Impairs Vascular Contractility in Male Offspring Mice With Transgenerational Effects.
Lei J, Zhao M, Yao S … +6 more , Lu M, Deng F, Xu T, Zhang M, Sun M, Gao Q
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41376593 · Publisher ↗
BACKGROUND: The application or excessive exposure to glucocorticoids constitutes a common adverse factor endured by intrauterine fetuses. Gestational glucocorticoids' exposure is intimately associated with the risk of po...
BACKGROUND: The application or excessive exposure to glucocorticoids constitutes a common adverse factor endured by intrauterine fetuses. Gestational glucocorticoids' exposure is intimately associated with the risk of postnatal vascular problems; however, whether the vascular problem can be transgenerationally inherited remains indistinct. In this study, a mouse model of gestational glucocorticoids' exposure was established, aiming to discover the abnormal phenotype of acquired vascular function of the offspring and clarify the epigenetic mechanism of the transgenerational transmission of the relevant abnormal phenotypes. METHODS: To model gestational glucocorticoid exposure, pregnant mice received intraperitoneal injections of dexamethasone (a synthetic glucocorticoid) on gestational days 12, 14, 16, and 18. Male offspring (F1) derived from dexamethasone group-exposed pregnancies were bred with wild-type females to generate F2 progeny, and this breeding strategy was repeated to produce F3 offspring. Adult male offspring from all 3 generations were subsequently analyzed. RESULTS: We observed that gestational dexamethasone group exposure induced a modest but consistent elevation in systolic blood pressure across F1 to F3 male offspring, accompanied by enhanced Ang II (angiotensin II)-mediated vascular contractility. Mechanistically, dexamethasone group exposure significantly reduced DNA methylation in the Agtr1a (Ang II receptor subtype A) gene promoter within F1 offspring vasculature, leading to upregulated Agtr1a expression and heightened oxidative stress via the AT1R (Ang II receptor 1)/NOX (nicotinamide adenine dinucleotide phosphate oxidase) 2/reactive oxygen species axis. This cascade potentiated Ang II-induced vascular contractility. Moreover, these acquired abnormal vascular problems can be stably inherited and transgenerationally transmitted through the alteration of the DNA methylation pattern of the Agtr1a gene in sperm. CONCLUSIONS: This study demonstrates that gestational glucocorticoids' exposure triggers transgenerational inheritance of vascular dysfunction in male offspring via DNA methylation reprogramming, providing direct evidence for the epigenetic transmission of acquired traits. These findings advance our understanding of intergenerational disease mechanisms and offer novel insights for clinical strategies aimed at mitigating the adverse effects of gestational glucocorticoid therapy.
Regulation of Insulin Transcytosis Across Endothelium in Metabolic Health and Disease.
Mineo C, Shaul PW
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41342145 · Publisher ↗
The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical rol...
The delivery of insulin to the skeletal muscle has a major influence on glucose disposal in muscle, where 80% of total body glucose disposal occurs. The skeletal muscle microvascular endothelial cells play a critical role in peripheral insulin sensitivity through their regulation of insulin delivery. Recent advancements in methodologies have provided in-depth views of the molecular mechanisms by which the endothelial cells regulate the delivery process. However, how the cellular machinery is modulated under physiological or pathological conditions remains largely unexplored. Conditions with estrogen deficiency and obesity are 2 situations that are closely associated with peripheral insulin resistance and type 2 diabetes in humans. It is of great interest to determine whether and how endothelial control of insulin delivery impacts the development of metabolic dysregulation under these and other conditions. This review aims to provide an overview of the molecular mechanisms governing insulin delivery to the skeletal muscle. The available evidence will be presented that the transcytosis of insulin across the endothelial cell monolayer in skeletal muscle plays a critical role in muscle insulin delivery, thereby having a major impact on overall glucose homeostasis. In vivo investigations with manipulation of mechanisms in endothelial cells will be summarized, and the current knowledge gaps will be presented. Interrogation of the role of the endothelium in insulin transport provides a paradigm in which insights are being gained about cellular actions of insulin, molecular transport by endothelial cells, and the intricacies of glucose homeostasis.
Unidirectional Shear Stress-Operated NOTCH/CXCR4 Molecular Switch Controls Semilunar Valve Maturation and Collagen Stratification.
Dai CR, Pham DH, Janani G … +3 more , Lin BY, Zhou B, Butcher JT
Arterioscler Thromb Vasc Biol · 2026 Feb · PMID 41342144 · Publisher ↗
BACKGROUND: Much is known about the genetic regulation of early valvular morphogenesis, but mechanisms governing later fetal valvular remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it...
BACKGROUND: Much is known about the genetic regulation of early valvular morphogenesis, but mechanisms governing later fetal valvular remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Apparent side-specific expression of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling directs the remodeling and maturation of valve leaflets. Here, we aim to determine how local hemodynamic stress regulates the maturation of fetal semilunar heart valves. METHODS: We identified strong ventricularis-specific expression of endocardial NOTCH1 and mesenchymal CXCR4 (C-X-C chemokine receptor type 4) during fetal valve stages. Valve cell-type specific conditional and mouse deletions were generated and analyzed in vivo consequences, which were then tested directly using ex vivo chick endocardial cells and valve organoids via gain and loss of function approaches. Samples were then quantitatively analyzed via histology, immunohistochemistry, and qRT-PCR (quantitative real-time polymerase chain reaction). RESULTS: We established that unidirectional laminar shear stress regulates CXCR4 via endocardial NOTCH signaling through upregulation of CXCR4 ligand SDF1 (stromal cell-derived factor 1). Global deletion and endocardium-derived mesenchymal cell-specific deletion of both resulted in hyperproliferative and thickened outflow tract valves. In addition, conditional ablation of also revealed that it promotes matrix remodeling and tissue compaction through inhibition of BMP (bone morphogenetic protein) and WNT signaling programs. CONCLUSIONS: High-magnitude unidirectional laminar shear stress is transduced by endocardial cells, turning on a NOTCH1/CXCR4 molecular switch. This switch stops the valve mesenchymal growth program by inhibiting WNT/BMP. Simultaneously, it also orchestrates valve condensation, mesenchymal cell differentiation, and ECM (extracellular matrix) remodeling. Taken together, our findings identify a novel molecular switch controlled by local hemodynamic cues that directs valve maturation robustly in a side-specific manner.
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