Arteriosclerosis, Thrombosis, And Vascular Biology[JOURNAL]
Sun
200 papers
Pulmonary Vascular Signaling in Pulmonary Hypertension: Potential Role of Endothelial Ca Signaling in Cellular Senescence and Inflammasome Activation.
Wang WT, Li X, Wang T … +5 more , Ferrizzi SA, Avchalumov Y, Thistlethwaite PA, Makino A, Yuan JX
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41815086 · Full text
This review focuses on describing the potential pathogenic roles of endothelial Ca and K signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and i...
This review focuses on describing the potential pathogenic roles of endothelial Ca and K signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and inflammasome activation. Ca influx through mechanosensitive and receptor-operated cation channels and Ca release from the endoplasmic reticulum are involved in upregulating the cell cycle inhibitors p53, p21, and p16 (which result in cellular senescence) by activating the AKT/mTORC1 (Ak strain transforming/mammalian target of rapamycin) pathway in lung vascular endothelial cells. A rise in cytosolic Ca concentration, resulting from Ca influx and release in lung vascular endothelial cells, is also necessary to activate both canonical (NLRP3 [nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3]) and noncanonical inflammasomes, thereby promoting vascular and perivascular inflammation. Furthermore, K efflux through multiple types of K-permeable channels and pores (eg, K ionophores, toxin-formed pores/channels, nonselective cation channels, and Ca-activated K channels) is sufficient for canonical (NLRP3) inflammasome activation. The senescent endothelial cells release senescence-associated secretory phenotype factors that subsequently cause endothelial-to-mesenchymal transition in adjacent endothelial cells and promote cell proliferation/migration in adjacent smooth muscle cells and (myo)fibroblasts, leading to vascular remodeling and occlusive intimal lesions, and pulmonary hypertension.
Deficiency of Modulates Vascular Smooth Muscle Cell Phenotype and Increases Neointima Formation.
Aherrahrou R, Reinberger T, Werner J … +9 more , Otto M, Al-Hasani J, Munoz-Venegas ML, Yin X, Mayr M, Civelek M, Schunkert H, Kessler T, Aherrahrou Z
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41815085 · Publisher ↗
BACKGROUND: The (zinc finger C3HC-type containing 1) gene has been linked to various cardiovascular traits, including coronary artery disease, blood pressure, and carotid intima-media thickness with opposing effects. Th...
BACKGROUND: The (zinc finger C3HC-type containing 1) gene has been linked to various cardiovascular traits, including coronary artery disease, blood pressure, and carotid intima-media thickness with opposing effects. This study aimed to investigate the role of ZC3HC1 in smooth muscle cell (SMC) biology and its contribution to neointima formation. METHODS: SMC phenotypes (proliferation and migration) were analyzed according to rs11556924 genotype, small interfering RNA-mediated knockdown of human ZC3HC1, or complete knockout of murine Zc3hc1. Transcriptomic profiling and contractile marker expression were used to define SMC states. The impact of complete gene loss on injury-induced neointima formation was examined in vivo using Zc3hc1 mice. Subcellular localization of murine NIPA (nuclear interaction partner of anaplastic lymphoma kinase; encoded by Zc3hc1) during the cell cycle was analyzed by immunofluorescence microscopy. RESULTS: The coronary artery disease-protective rs11556924-T allele was associated with reduced expression and enhanced SMC migration. knockdown in human SMCs replicated this phenotype, increasing migration and proliferation, and leading to CCNB1 (cyclin B1) accumulation with reduced expression of contractile markers. Following arterial injury, mice exhibited exaggerated neointima formation and enhanced SMC migration. In contrast to small interfering RNA experiments, complete loss resulted in reduced SMC proliferation and lower CCNB1 levels. Transient knockdown of in wild-type mouse SMCs increased proliferation, recapitulating findings in human cells. Immunofluorescence revealed colocalization of NIPA and CCNB1 at the cleavage furrow, suggesting a role in mitotic exit. CONCLUSIONS: ZC3HC1 acts as a dosage-sensitive modulator of SMC phenotype. Partial reduction promotes a synthetic, proliferative state and neointima formation, while complete loss induces a quiescent phenotype. These findings provide mechanistic insight into the paradoxical clinical associations of the rs11556924-T allele and identify ZC3HC1 as a potential target for modulating SMC phenotypes in vascular disease.
Mechanisms Linking Sleep-Disordered Breathing and Cardiometabolic Disease Risk.
Gomez R, Sun W, Shyy M … +5 more , Ou YJ, Sihota A, Liu B, Mesarwi O, Malhotra A
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41783932 · Full text
Sleep-disordered breathing (SDB) is a group of disorders defined by intermittent closure or narrowing of the upper airway, caused either by mechanical obstruction or dysregulation of the respiratory centers in the brains...
Sleep-disordered breathing (SDB) is a group of disorders defined by intermittent closure or narrowing of the upper airway, caused either by mechanical obstruction or dysregulation of the respiratory centers in the brainstem. The effects of SDB on cardiovascular and metabolic health and disease have been an area of growing interest. Many studies have shown mechanistic links between physiological changes seen in SDB and important cardiometabolic outcomes. In particular, SDB induces alterations in autonomic function, swings in intrathoracic pressure, systemic inflammation, sleep fragmentation, and oxidative stress, with diverse effectors including alterations in cellular gene expression, for example, through microRNA and hypoxia-inducible factor 1, changes in the gut microbiome, and many others. Ultimately, these mechanistic pathways have implications on vascular and myocardial dysfunction, hypertension, insulin sensitivity, lipid metabolism, and weight gain. Several treatment modalities exist for SDB, and are chosen based on the specific disease process and patient preference/tolerance. These therapies result in an improvement in symptoms related to SDB severity and varying levels of cardiometabolic disease risk mitigation. In this review, we will present some important mechanisms of SDB that increase the risk for cardiometabolic disease, and we will discuss therapies and their intended targets.
Comparison of Cardiovascular Events in Patients Receiving Concomitant Clopidogrel and Proton Pump Inhibitors Classified by CYP2C19 Inhibitory Potency.
Kim S, Park J, Chen HY … +15 more , Setiawan CH, Lee H, Martin B, Lee KJ, Hripcsak G, Hsu JC, Nagy P, Kim S, Nguyen PA, Thanh-Phuc P, Muhtar MS, Hsu MH, Shin WG, You SC, Seo SI
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41783931 · Full text
BACKGROUND: Proton pump inhibitors (PPIs) may potentially reduce clopidogrel's antiplatelet effect and increase cardiovascular risk. The degree of CYP (cytochrome P450) 2C19 inhibition varies among PPIs. Few studies have...
BACKGROUND: Proton pump inhibitors (PPIs) may potentially reduce clopidogrel's antiplatelet effect and increase cardiovascular risk. The degree of CYP (cytochrome P450) 2C19 inhibition varies among PPIs. Few studies have evaluated individual PPIs by CYP2C19 inhibition strength across countries. This study aimed to compare the incidence of cardiovascular events between strong CYP2C19-inhibiting potency and weak CYP2C19-inhibiting potency (weak or non-CYP2C19-inhibiting PPIs) in patients receiving clopidogrel. METHODS: We conducted an international observational cohort study using 14 databases from the United States, South Korea, and Taiwan. We included patients aged ≥18 years who received clopidogrel with PPIs from 1985 to 2023. PPIs were classified into strong CYP2C19-inhibiting PPIs and weak or non-CYP2C19-inhibiting PPIs based on CYP2C19 inhibition. We compared the hazard ratios and 95% CIs for major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, using the Cox proportional hazards model after 1:1 propensity score matching. Secondary outcomes included cardiovascular mortality, myocardial infarction, stroke, and all-cause mortality. A random-effects model calculated pooled hazard ratios and 95% CIs. Only databases meeting all diagnostic criteria were included in the meta-analysis. RESULTS: Large-scale propensity score matching identified 166 005 patient pairs. During the 365-day follow-up, the risk of major adverse cardiovascular events did not differ significantly between patients receiving clopidogrel plus strong CYP2C19-inhibiting PPIs and those receiving clopidogrel plus weak or non-CYP2C19-inhibiting PPIs (17.63 per 1000 person-years versus 16.82 per 1000 person-years; calibrated hazard ratio, 1.00 [95% CI, 0.79-1.26]). No significant difference was observed in the risk of secondary outcomes (calibrated hazard ratio, cardiovascular mortality 1.10 [95% CI, 0.87-1.39], myocardial infarction 0.98 [95% CI, 0.81-1.19], stroke 1.05 [95% CI, 0.87-1.27], and all-cause mortality 1.18 [95% CI, 0.93-1.50]). CONCLUSIONS: Concomitant use of clopidogrel and strong CYP2C19-inhibiting PPIs was not associated with a higher cardiovascular risk compared with concomitant use of clopidogrel and weak or non-CYP2C19-inhibiting PPIs. This large-scale study does not support the clinical significance of potential interactions between PPIs and clopidogrel.
ELABELA Protects Against Thoracic Aortic Dissection by Maintaining Vascular Smooth Muscle Cells Homeostasis and Regulating NETosis.
Zheng F, Geng Z, Ye C … +11 more , Hao M, Sha M, Shan H, Zhou Y, Jiang A, Hou W, Chen A, Susan BD, Wang J, Li Q, Xiong X
Arterioscler Thromb Vasc Biol · 2026 May · PMID 41783930 · Publisher ↗
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. EL...
BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1-related receptor protein). However, the effects of ELA on TAD formation and development remain elusive. METHODS: Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA. RESULTS: ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs' formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β-related NETs' formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD. CONCLUSIONS: We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β-related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.
Platelet mTOR Is a Regulator of Sterile Immunothrombosis.
Denorme F, Portier I, Castro H … +9 more , Ajanel A, Kosaka Y, Benzon H, De Araujo CV, Souvenir R, Abel ED, Weyrich AS, Rondina MT, Campbell RA
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41783929 · Full text
BACKGROUND: Immunothrombosis entails a tight interplay between thrombotic and inflammatory pathways and plays a pathological role in ischemic stroke and venous thrombosis. mTOR (mechanistic target of rapamycin) is a cano...
BACKGROUND: Immunothrombosis entails a tight interplay between thrombotic and inflammatory pathways and plays a pathological role in ischemic stroke and venous thrombosis. mTOR (mechanistic target of rapamycin) is a canonical serine/threonine kinase and is involved in platelet signaling and thrombus stabilization in vitro. Activation of platelet mTOR is upregulated in aging and inflammatory disorders. However, its role in vivo is poorly understood. METHODS: We used mice specifically lacking mTOR in platelets and assessed platelet activation and platelet-leukocyte interactions in response to platelet agonists. In addition, we examined the role of platelet mTOR in models of hemostasis, thrombosis, inflammatory bleeding, and sterile immunothrombosis, including ischemic stroke and venous thrombosis. RESULTS: Platelets lacking mTOR had a small activation defect and had lower procoagulant potential. In the absence of mTOR, activated platelets interacted less with monocytes and neutrophils. In addition, platelet mTOR regulated platelet-mediated neutrophil activation. Platelet cytoplasmic calcium flux was similar in the presence and absence of mTOR, whereas clot retraction was reduced in the absence of platelet mTOR, suggesting a role for mTOR in selectively regulating Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent pathways involved in sustained platelet function. In vivo, the absence of platelet mTOR did not impact hemostasis, inflammatory bleeding in the lung and skin, or FeCl-induced arterial thrombosis. In contrast, platelet-specific mTOR knockout mice were protected from ischemic stroke brain injury and stasis-induced venous thrombosis due to reduced thrombosis and inflammation. CONCLUSIONS: Platelet mTOR is a critical mediator of sterile immunothrombosis, although it is dispensable for hemostasis in mice. The immunothrombotic-specific effects of mTOR make it an attractive therapeutic target with a good safety profile.
Remembering Dr Janet T. Powell.
Schmidt AM, Hegele RA
Arterioscler Thromb Vasc Biol · 2025 Aug · PMID 41779021 · Publisher ↗
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Valvular Leaflets Are Not Innocent Bystanders: Divergent Fibrotic Remodeling Accompanies Functional Mitral and Tricuspid Regurgitation.
Shi H, Shu S, Chen X … +9 more , Chen X, Wang X, Wang W, Wang X, Song S, Hu H, Han K, Song J, Liu J
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41744092 · Full text
BACKGROUND: Functional valve regurgitation (FVR) progression has traditionally been attributed to external anatomic alterations, without consideration of leaflet-intrinsic pathology. Emerging evidence now implicates valv...
BACKGROUND: Functional valve regurgitation (FVR) progression has traditionally been attributed to external anatomic alterations, without consideration of leaflet-intrinsic pathology. Emerging evidence now implicates valvular leaflets as active contributors rather than passive bystanders in FVR pathogenesis. Systematic investigations into leaflet-specific pathomechanisms remain absent for major FVR subtypes, particularly functional mitral regurgitation (FMR) and functional tricuspid regurgitation (FTR). METHODS: The association of FVR with clinical parameters was analyzed in a heart transplantation cohort. Comprehensive microscopic pathology evaluated fibrotic remodeling in mild, moderate, and severe FMR/FTR leaflets, validated in an independent bulk RNA sequencing cohort (FMR/FTR: n=41 each). Single-cell RNA sequencing was performed on 19 FVR leaflets (FMR: 3 mild/2 moderate/3 severe; FTR: 5 mild/3 moderate/3 severe). Subsequent analyses (cluster annotation, cellular proportions, trajectory inference, and cell-cell communication) explored cellular mechanisms of fibrotic remodeling in FVR, focusing on unique and shared changes between FMR and FTR. Histopathology and bulk transcriptomics validated single-cell RNA sequencing findings. Primary valvular endothelial cells and valvular interstitial cells from FVR patients underwent pharmacological intervention. A monocrotaline-induced rat pulmonary hypertension model established FTR, followed by pharmacological treatment to assess leaflet-directed therapy efficacy. RESULTS: Fibrotic leaflet remodeling scores independently predicted FMR/FTR severity with high precision and significantly improved prediction beyond anatomic anomalies. Fibrotic remodeling showed divergent mechanisms between FMR and FTR. In FMR, suppressed retinoic acid metabolism drove antifibrotic-to-neutral valvular interstitial cell transition. In FTR, impaired IFN (interferon) signaling promoted antifibrotic-to-profibrotic valvular interstitial cell transdifferentiation, worsened by endothelial-to-mesenchymal transition-derived profibrotic valvular endothelial cells. Targeted PDK4 (pyruvate dehydrogenase kinase 4) upregulation or IFN signaling activation reduced FTR severity in vitro and in vivo. CONCLUSIONS: Leaflet-specific organic fibrotic remodeling actively involves FVR beyond functional adaptation, with distinct fibrotic mechanisms in FMR versus FTR. PDK4 and IFN modulation demonstrate therapeutic potential for FTR.
Adenosine-to-Inosine (A-to-I) RNA Editing by ADAR1 to Control RNA Sensing in Cardiovascular Disease.
Weldy CS, Li JB, Quertermous T
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41744067 · Full text
Across biology, organisms have retained a mechanism to diversify the RNA transcriptome through RNA editing. Mediated by ADAR (adenosine deaminase acting on RNA) enzymes, Adenosines in double-stranded RNA (dsRNA) structur...
Across biology, organisms have retained a mechanism to diversify the RNA transcriptome through RNA editing. Mediated by ADAR (adenosine deaminase acting on RNA) enzymes, Adenosines in double-stranded RNA (dsRNA) structures can be edited to Inosines (adenosine-to-inosine edit). Although this can change the amino acid sequence if it occurs in a coding sequence of mRNA, the majority of RNA editing in mammalian cells is found in noncoding repetitive elements. These repetitive elements have a predisposition to form long dsRNA structures that can mimic a dsRNA virus. Since the initial discoveries of RNA editing over 30 years ago, investigators have now identified ADAR1 to play a crucial role in suppressing innate immune activation and type I interferon signaling. Through adenosine-to-inosine editing, these dsRNA change their conformational structures and evade activation of the innate immune dsRNA sensor, MDA5 (melanoma differentiation-associated gene 5; gene symbol ). In human disease, although rare loss-of-function variants of ADAR1 have been associated with severe autoimmune disease, there has also been a rapid advance in our understanding of this molecular pathway in common complex diseases. We now understand that common genetic variants can impact RNA editing frequencies, and variants that decrease RNA editing are associated with an increase in risk of numerous autoinflammatory disorders as well as coronary artery disease. This rapid advance in our understanding of the genetic determinants of RNA editing and coronary artery disease has been mirrored by new discoveries in molecular biology, where deficient RNA editing within the vascular wall and smooth muscle cell now highlights endogenous RNA sensing by MDA5 as a causal mechanism of coronary artery disease and other vascular disorders. Here, in this review, we provide a focused look at major advances in RNA editing and cardiovascular disease and put these discoveries into historical context with a goal to map the next steps to advance these molecular pathways to new therapeutic discovery.
Hepatocyte-Specific Knockout of YAP Protects Against Atherosclerosis via Inhibition of ANGPTL3 in Mice.
Hou Y, Zhang X, Sun X … +4 more , Qin Q, Jia M, Su X, Chen Y
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41744066 · Publisher ↗
BACKGROUND: Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic card...
BACKGROUND: Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. METHODS: Hyperlipidemia models were generated in apoE knockout (apoE) mice or mice injected with adeno-associated virus 8-D377Y-mPCSK9, which degrades and deletes LDLR (low-density lipoprotein receptor), by being fed a high-cholesterol diet for 12 weeks. We measured the expression level of hepatic YAP in these apoE mice. Next, we created YAP (hepatocyte-specific deletion of Yes-associated protein) apoE mice to further determine the role of YAP in hyperlipidemia and atherosclerosis. AML12 (alpha mouse liver 12) cells and mice injected with AAV8-D377-mPCSK9 (adeno-associated virus 8 carrying the D377Y mutant of mouse proprotein convertase subtilisin/kexin type 9) or YAPapoE mice were used to elucidate its mechanism. Finally, apoE or LDLR knockout (LDLR) mice were used to observe the therapeutic efficacy of adeno-associated virus 8-Alb (albumin)-shYAP (short hairpin RNA targeting for YAP) for hyperlipidemia and atherosclerosis. RESULTS: High-cholesterol diet-fed apoE mice showed increased levels of YAP in the liver. Further investigation indicated that YAPapoE mice exhibited lighter hyperlipidemia and atherosclerosis than YAPapoE mice fed with a high-cholesterol diet. Conversely, hepatocyte-specific overexpression of YAP (5S) deteriorated hyperlipidemia and atherosclerosis in high-cholesterol diet-fed apoE mice. Furthermore, the lipid-lowering effect of YAP deficiency in hepatocytes was independent of LDLR. Hepatocyte-specific overexpression of ANGPTL3 (angiopoietin-like 3) aggravated hyperlipidemia and atherosclerosis in YAPapoE mice, indicating that ANGPTL3 is responsible for the function of YAP in hyperlipidemia. Mechanistically, YAP upregulated ANGPTL3 via TEAD (TEA domain family member) 4 in hepatocytes independent of LDLR. Notably, adeno-associated virus 8-Alb-shYAP lowered lipid levels in apoE or LDLR mice. CONCLUSIONS: Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia.
Correction to: Association Between Alternative Complement Pathway and Carotid Plaque and the Underlying Gut Microbial and Inflammatory Biomarkers: A Cohort Study.
Chen H, Lu Z, Xiao C … +6 more , Wang X, Xi Y, Yan Y, Zheng JS, Chen YM, Deng K
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41739912 · Publisher ↗
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Considerations in the Use of Mouse Models of Vascular and Valvular Calcification.
Hsu JJ, Li Q, Tintut Y … +1 more , Demer LL
Arterioscler Thromb Vasc Biol · 2026 Mar · PMID 41739911 · Full text
CLINICAL PROBLEM: Vascular and valvular calcification significantly contributes to cardiovascular morbidity, particularly in patients with diabetes, atherosclerosis, advanced age, and chronic kidney disease. Currently, t...
CLINICAL PROBLEM: Vascular and valvular calcification significantly contributes to cardiovascular morbidity, particularly in patients with diabetes, atherosclerosis, advanced age, and chronic kidney disease. Currently, there are no effective treatments to prevent or reverse calcification, emphasizing the urgent need for robust preclinical models to help identify therapeutic targets and strategies. RECOMMENDATIONS: Preclinical models for vascular and valvular calcification should accurately reflect human disease pathology and progression, ideally including the influence of key underlying conditions and diseases (age, diabetes, renal disease, and hyperlipidemia), as well as sexual dimorphism, each of which may require a different model. Standardized and reproducible end points are essential, with preference for assessments that align with clinically utilized modalities (eg, computed tomography and echocardiography). SUMMARY: Murine models of cardiovascular calcification described herein have contributed substantially to our understanding of cardiovascular calcification though the translation toward clinically impactful therapies has, thus far, been limited. Improving clinical translation demands the use of models that replicate human comorbidities, disease progression, and outcomes. Further development of improved models, particularly those that demonstrate clinically important features such as plaque rupture, will facilitate effective translation of therapeutic strategies to clinical practice.
When the Clock Breaks Character: Bmal1 as a Driver of Vascular Calcification in Diabetes.
Iruela-Arispe ML
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41711029 · Publisher ↗
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Renin-Angiotensin-Aldosterone System in Preeclampsia: Pathophysiological Insights and Links to Vascular Dementia.
Lutshumba J, Mirsky E, Bullens KA … +3 more , Smith EG, Ndashaala EL, Finch R
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41711028 · Full text
Preeclampsia, a condition characterized by new-onset hypertension during pregnancy and ≥1 indices of organ damage, is a major driver of both short- and long-term maternal health outcomes. Individuals with a history of pr...
Preeclampsia, a condition characterized by new-onset hypertension during pregnancy and ≥1 indices of organ damage, is a major driver of both short- and long-term maternal health outcomes. Individuals with a history of preeclampsia are at increased risk for cardiovascular, renal, and other chronic diseases. Recent studies have linked preeclampsia history with increased risk of dementia later in life, underscoring the importance of new guidelines emphasizing blood pressure control to reduce the risk of cognitive decline. Unfortunately, neither the mechanisms underlying the causes of preeclampsia nor their links with cognitive function are well understood. Vascular contributions to cognitive impairment and dementia are a type of dementia caused by reduced cerebral blood flow, often resulting from vascular dysfunction associated with small vessel damage or chronic hypertension. The renin-angiotensin-aldosterone system (RAAS) is a hormone system with a major role in regulating blood pressure, fluid homeostasis, and vascular function inside and outside of pregnancy. The RAAS is markedly activated during pregnancy; preeclampsia is associated with disruptions in the normal activity of the RAAS, including excessive Ang (angiotensin) II type 1 receptor signaling, and loss of protective effects of Ang-(1-7) and Ang II type 2 receptors. Preexisting hypertension may impair the normal RAAS response to pregnancy, increasing susceptibility to vascular damage both during and after pregnancy. Results from human and animal studies indicate that dysregulation of the RAAS is a shared pathway underlying vascular dysfunction in both preeclampsia and vascular contributions to cognitive impairment and dementia, suggesting a mechanistic link between these 2 conditions. Persistent endothelial damage, impaired vascular remodeling, and chronic activation of Ang II type 1 and mineralocorticoid receptor signaling may increase long-term risk. This connection underscores the importance of monitoring and managing blood pressure during pregnancy and in women with a history of preeclampsia to mitigate the risk of dementia.
Prdm16 Amplifies Notch Signaling and Suppresses Venous Lineage Specification to Prevent Arteriovenous Malformations During Vascular Development.
Van Wauwe J, Janarthanan P, Craps S … +16 more , Kc A, Asuncion L, Vrancaert P, Kemps H, Daems M, Finck C, Wright S, Müller C, Leigh ND, Renné T, Ola R, Panáková D, Frye M, MacRae CA, Luttun A, Beerens M
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41711027 · Full text
BACKGROUND: TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in th...
BACKGROUND: TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and polymorphisms are associated with coronary artery disease. METHODS: Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR (real-time quantitative polymerase chain reaction), Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations. RESULTS: Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development. CONCLUSIONS: Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations.
Role of Depression and Anxiety in Peripheral Artery Disease: Correlates, Outcomes, and Considerations for Treatment.
Callegari S, Mubarak E, Romain G … +3 more , Golledge J, Mena-Hurtado C, Smolderen KG
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41711026 · Full text
Peripheral artery disease (PAD) affects millions worldwide and is associated with high mortality, major amputations, and detrimental effects on functional and health status. PAD management is multifactorial and encompass...
Peripheral artery disease (PAD) affects millions worldwide and is associated with high mortality, major amputations, and detrimental effects on functional and health status. PAD management is multifactorial and encompasses addressing cardiovascular and metabolic risk factors, improving symptoms and vessel patency through exercise therapy or revascularization, and medications. PAD frequently develops under complex biopsychosocial circumstances, and those same mechanisms impact treatment and outcomes. In these contexts, depression and anxiety play a significant role and are known to be associated with a higher risk of developing PAD and worse disease and treatment outcomes. Incorporating depression and anxiety assessment and treatment can complement the traditional approach to cardiovascular disease management to improve outcomes, given that we know they influence the development and progression of PAD and its treatment. In this review, we evaluate various biological and behavioral mechanisms linking depression, anxiety, and PAD, as well as the role of depression and anxiety in treatment planning. We stress the importance of considering these disorders when managing PAD with both medical and surgical approaches and discuss future avenues for a holistic, team-based, and multidisciplinary approach to improve long-term outcomes in individuals with PAD.
Screening, Diagnosis, and Management of Pediatric Hypertriglyceridemia: A Scientific Statement From the American Heart Association.
Peterson AL, Ashraf AP, Bachman J … +12 more , Hegele RA, Rashad M, South AM, Tran AH, Zachariah J, Wong JP, American Heart Association Cardiovascular Disease Prevention Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young, Council on Clinical Cardiology, Council on Genomic and Precision Medicine, Council on Lifestyle and Cardiometabolic Health, Council on Basic Cardiovascular Sciences, Council on Cardiovascular and Stroke Nursing
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41705332 · Publisher ↗
Pediatric hypertriglyceridemia is common in youths, affecting 10% to 20% of US children and adolescents, and is increasingly recognized because of its association with obesity, insulin resistance, and steatotic liver dis...
Pediatric hypertriglyceridemia is common in youths, affecting 10% to 20% of US children and adolescents, and is increasingly recognized because of its association with obesity, insulin resistance, and steatotic liver disease. Hypertriglyceridemia can lead to life-threatening acute pancreatitis, and prolonged exposure may increase risk of atherosclerotic cardiovascular disease. Screening for pediatric dyslipidemia has been recommended by a number of society guidelines; however, screening rates remain suboptimal. Treatment includes a multidisciplinary approach focused on increasing physical activity, dietary interventions, and pharmacotherapy. This scientific statement outlines triglyceride metabolism and the pathophysiology of hypertriglyceridemia and provides an evidence-based review of the current literature on the screening, diagnosis and management of pediatric hypertriglyceridemia. This review highlights the need for additional research for effective lifestyle and pharmacotherapy for the treatment of pediatric hypertriglyceridemia.
Murine Aortopulmonary Shunt Model of Flow-Driven Pulmonary Hypertension-Brief Report.
Cai D, Zhou R, Fujise K … +1 more , Chen SY
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41674466 · Full text
BACKGROUND: Chronic left-to-right shunting, as occurs with congenital heart disease or persistent ductus-like flow, exposes pulmonary circulation to sustained high-flow shear and pulsatile pressure and causes severe, flo...
BACKGROUND: Chronic left-to-right shunting, as occurs with congenital heart disease or persistent ductus-like flow, exposes pulmonary circulation to sustained high-flow shear and pulsatile pressure and causes severe, flow-mediated arteriopathy. A scalable, minimally invasive mouse model that reproduces this hemodynamic trigger is needed to enable mechanistic dissection in a genetically tractable system. METHODS: An ultrasound-guided transcatheter aortopulmonary shunt procedure was developed to create ductus-like communication between the aortic arch and pulmonary artery. Shunt formation and patency were confirmed by B-mode echocardiography with color and pulsed-wave Doppler. Hemodynamics and right ventricular function were assessed by transthoracic echocardiography and closed-chest micromanometer catheterization at 1 month after surgery. A subset of animals was analyzed at 14 days for early endothelial plasticity. Bulk RNA sequencing of pulmonary arteries was performed to define transcriptional remodeling associated with shunt-driven disease. RESULTS: Transcatheter aortopulmonary shunt produced a sustained left-to-right overcirculation with Doppler-confirmed shunt flow, which induced pulmonary artery hypertension with elevated right ventricular systolic pressure, increased pulmonary vascular load, and progressive right ventricular dilation and dysfunction. Histological analyses demonstrated robust pulmonary arterial remodeling, including medial muscularization and thickening, adventitial expansion, and perivascular fibrosis, accompanied by right ventricular cardiomyocyte hypertrophy and increased myocardial fibrosis. Transcriptomic profiling of pulmonary arteries revealed broad differential gene regulation consistent with pulmonary artery hypertension pathobiology, including inflammatory, proliferative, and profibrotic responses and increased mesenchymal/smooth muscle marker expression. Costaining endothelial and mesenchymal markers supported endothelial phenotypic transition within the remodeled pulmonary arterial wall. CONCLUSIONS: Transcatheter aortopulmonary shunt establishes a minimally invasive, reproducible murine model of shunt-driven pulmonary artery hypertension triggered by flow-mediated arteriopathy. This platform provides a versatile tool to interrogate flow-sensing mechanisms and to evaluate therapies targeting both vasoreactivity and structural remodeling in pulmonary artery hypertension.
Sleep-Aligned Extended Overnight Fasting Improves Nighttime and Daytime Cardiometabolic Function.
Grimaldi D, Reid KJ, Abbott SM … +2 more , Knutson KL, Zee PC
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41674465 · Full text
BACKGROUND: Time-restricted eating has gained attention for its potential cardiometabolic health benefits. Existing time-restricted eating approaches may have limited adherence and sustainability due to fixed fasting win...
BACKGROUND: Time-restricted eating has gained attention for its potential cardiometabolic health benefits. Existing time-restricted eating approaches may have limited adherence and sustainability due to fixed fasting windows with prolonged fasting duration before sleep, or they involve self-selected fasting windows without specifying the duration relative to sleep, a critical period for cardiometabolic regulation. We hypothesized that an individualized approach that extended overnight fasting duration by 3 hours in alignment with habitual sleep time (last meal ≥3 hours before sleep) would enhance nighttime autonomic balance, decrease blood pressure and heart rate, increase blood pressure per hour dipping, and glucose regulation compared with a control group maintaining habitual eating patterns. METHODS: In this randomized parallel-arm controlled trial, 39 overweight/obese participants (36-75 years) completed either an extended overnight fasting intervention (13-16-hour fasting) or a control condition (habitual fast of 11-13 hours). Both groups dimmed lights 3 hours before bedtime. The intervention duration was 7.5 weeks. RESULTS: Compared with control, extended overnight fasting intervention significantly improved the coprimary outcome of nighttime dipping of diastolic blood pressure, but not the Matsuda Index of insulin sensitivity. extended overnight fasting improved secondary measures of nighttime autonomic function and morning oral glucose tolerance, including lower nighttime heart rate, higher heart rate variability, lower nighttime cortisol, and during the Oral Glucose Tolerance Test, lower glucose level, and higher 30-minute insulinogenic index, indicating improved acute insulin response. CONCLUSIONS: Extending overnight fasting duration by 3 hours in alignment with sleep improved cardiometabolic health in middle-aged/older adults by strengthening coordination between circadian- and sleep-regulated autonomic and metabolic activity. This sleep-aligned time-restricted eating approach represents a novel, accessible lifestyle intervention with promising potential for improving cardiometabolic function.
Systemic Loss of FKBPL Uncovers Diabetes-Dependent Pathways of Myocardial and Vascular Injury.
Alqudah A, Edgar KS, O'Neill KM … +10 more , McNally R, Zhand S, Le N, Chhor M, Short A, Kavurma MM, Lopez-Campos GH, Robson T, Grieve DJ, McClements L
Arterioscler Thromb Vasc Biol · 2026 Apr · PMID 41674464 · Publisher ↗
BACKGROUND: Impaired angiogenesis underpins cardiovascular disease, particularly in people with diabetes; however, molecular mechanisms are still poorly understood. This study aims to decipher the role of an emerging ant...
BACKGROUND: Impaired angiogenesis underpins cardiovascular disease, particularly in people with diabetes; however, molecular mechanisms are still poorly understood. This study aims to decipher the role of an emerging antiangiogenic protein, FKBPL (FK506-binding protein-like), on cardiac structure and function, vascular integrity, and inflammatory signaling in in vivo and in vitro models of diabetes. METHODS: In vivo, FKBPL transgenic mice () were used to examine the metabolic and cardiovascular function and FKBPL-mediated mechanisms in streptozotocin-induced diabetes. In addition, comprehensive in vitro assessments of endothelial function and mechanisms were performed in normal/high-glucose and high/low-FKBPL conditions. RESULTS: mice show signs of early cardiac remodeling (increased E/A [early-to-atrial filling velocity ratio] ratio, =0.047, and cardiomyocytes size, =0.0018; reduced collagen deposition, =0.013; mRNA reduction, =0.0028) and aberrant expression of cardiac vascular dysfunction proteins (ICAM-1 [intercellular adhesion molecule 1], <0.001, SIRT-1 [sirtuin 1]; <0.001). Proinflammatory cardiac profile was prominent in murine hearts with increased protein expression of ICAM-1, IL (interleukin)-12p40, IL-15, IL-22, LIF (leukemia inhibitory factor), lipocalin-2, MMP (matrix metalloproteinase)-3/-9, periostin, serpin E1, and VCAM-1 (vascular cell adhesion molecule 1), which were decreased in diabetes. In diabetic mice with low FKBPL expression, glucose metabolism deteriorated, whereas vascular dysfunction improved. In normal glucose conditions, FKBPL knockdown in human aortic endothelial cells reduced VE-cadherin (vascular endothelial cadherin; =0.0016) and impaired endothelial barrier (<0.001). In high-glucose conditions, endothelial FKBPL knockdown improved angiogenesis, however overexpression of FKBPL reduced angiogenesis by inhibiting the FGF (fibroblast growth factor) and PDGF (platelet-derived growth factor) pathways (<0.001) and increasing proinflammatory pathways (TGF [transforming growth factor]-β, <0.001; leukocyte migration, =0.033; IL-7 signaling, =0.039), by upregulating microRNA (miR)-29b-3p (=0.01) and miR-302b-5p (=0.03), likely via CD44 (cluster of differentiation). FKBPL-based peptide mimetic, AD-01 (1 nM), in high-glucose conditions, upregulated endothelial and mRNA expression, independent of miR-302b-5p. CONCLUSIONS: FKBPL plays an important role in glucose metabolism, endothelial function, angiogenesis, cardiac inflammation and function, and could be explored as a therapeutic target of cardiovascular disease both in nondiabetes and diabetes settings using precision medicine approach.
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