Search Results (226)

Nutraceuticals are emerging as promising agents for the prevention and treatment of atherosclerosis, particularly in light of the limitations associated with current pharmacotherapies. Pomegranate-derived polyphenols, especially punicalagin (PC), possess multiple cardioprotective properties. However, their direct biological effects are constrained by poor absorption and low bioavailability. Instead, many of their actions are mediated by gut microbiota-derived metabolites known as urolithins. Despite this, the roles of PC and its metabolites in atherosclerosis remain inadequately defined. The objective of this study was to investigate the anti-atherogenic effects and underlying mechanisms of PC and its major metabolites—ellagic acid and urolithins A, B, C, and D—using in vitro and in vivo approaches. In vitro, these compounds broadly inhibited key pro-atherogenic processes in macrophages and endothelial cells, including reactive oxygen species production and inflammatory gene expression, with notable metabolite-specific differences. Urolithin A (UA), identified as the most effective compound, was further evaluated in LDL receptor-deficient mice fed a high-fat diet. UA supplementation improved peripheral blood immune cell profile, reduced atherosclerotic plaque burden and inflammation, and enhanced markers of plaque stability. RNA sequencing of the thoracic aorta revealed key molecular pathways underlying the protective actions of UA. Collectively, these findings highlight the therapeutic potential of PC-derived metabolites, particularly UA, in combating atherosclerosis and support the need for future human clinical studies. Full article

Background/Objectives: Nuclear receptor corepressors NCOR1 and NCOR2 are key regulators of transcriptional repression, chromatin remodelling, and immunometabolic signalling. While NCOR1 has already been linked to vascular biology, its relevance in abdominal aortic aneurysm (AAA) remains unclear, particularly for NCOR2. This study aimed to investigate the expression, cellular localisation, and molecular interactions of NCOR1/2 in human AAA tissue. Methods: Human AAA samples (elective and ruptured) (n = 45) and non-aneurysmal control aortas (n = 18) were obtained from our Swiss Vascular Biobank. Transcriptomic profiling was performed using ribosomal RNA-depleted RNA sequencing. Differential expression and correlation analyses were performed using DESeq2/EdgeR and Spearman rank correlation with Benjamini–Hochberg correction. Cellular localisation was assessed through immunohistochemistry (IHC). Results: Bulk transcriptomic analyses showed no significant differences in NCOR1 or NCOR2 expression between AAA and controls. IHC revealed that NCOR1 was found in endothelial cells (ECs), smooth muscle cells (SMCs), and inflammatory infiltrates, while NCOR2 was primarily associated with macrophages. Correlation analyses suggest that NCOR1 interacts with various cellular markers, proteolytic enzymes, inflammatory mediators, and epigenetic regulators, including the lncRNA MALAT1. NCOR2 showed distinct associations with remodelling enzymes, TGFB1 signalling, selective epigenetic modifiers, and lncRNA H19. Conclusions: The lack of transcriptional differences in NCOR1 and NCOR2 between AAA and controls does not exclude cell-type-specific regulation or functional relevance. The specific cellular distributions and molecular associations in human AAA imply that NCOR1 and NCOR2 play non-redundant roles in vascular remodelling, inflammation, and epigenetic regulation. Our findings highlight NCOR pathways as potential modulators of AAA pathophysiology and promising targets for future therapies. Full article

Currently, silicone is a common material used in medical research and biomedical applications. This research aims to characterize extra-soft platinum silicone (shore A 00 50) and compare its mechanical behavior with that of the human thoracic aorta. By developing molds to get samples, for tensile testing according to ISO 37 and ASTM D412, and for compression testing according to ISO 7743 and ASTM D575, using a universal testing machine for tensile and compression tests, and applying digital image correlation (DIC) algorithms, the mechanical properties were characterized in a total of 10 tensile samples and 6 compression samples. The results show an ultimate tensile strength up to 1.77 ± 0.12 MPa in the ASTM samples and 2.10 ± 0.14 MPa in the ISO samples; alongside an incremental elastic module of 80.08 ± 7.94 kPa and 117.98 ± 11.39 kPa; finally, an elongation at break of 1114.49 ± 76.77% and 936.08 ± 63.56%, corresponding to the values of a healthy thoracic aorta. The replica of the thoracic aorta in this material was developed by a brush method, with a thickness of 1.82 mm, a length from the aortic arch to the descending aorta of 200.49 mm, and diameters of 20.45 and 16.05 mm for the ascending and descending aorta, respectively. Full article

The use of computational fluid dynamics (CFD) to study hemodynamics in arteries offers significant potential for addressing complex flow problems. Due to its enhanced performance hardware and software, CFD has become an important approach for studying hemodynamics in human arteries. This approach is utilized to investigate hemodynamics and forecast risk factors for atherosclerotic lesion development and progression, including circulatory flow, and to analyze local flow fields and flow profiles resulting from geometric changes. This foundational study will aid in analyzing blood flow behavior through the abdominal aorta and the origin and courses of renal arteries, as well as investigating the causes of disorders such as atherosclerosis and hypertension. The current study investigates three idealized abdominal aorta–renal artery junction models under varying blood pressure settings. Materialise software V19 was used to extract the geometry data to create idealized 3D abdominal aorta–renal branching models. Unsteady flow simulations were performed in ANSYS Fluent, utilizing rigid walls and Newtonian and Carreau–Yasuda viscosity conditions. Oscillatory shear index (OSI) and Time-averaged wall shear stress (TAWSS) were measured to enhance understanding of atherosclerotic plaque formation and progression. Also, the effect of geometric change at the bifurcation area was explored, and it was discovered that this location causes considerable vortex forming zones. The evident velocity reduction and backflow development were seen, reducing shear stress. The findings indicate that low TAWSS < 0.4 Pa and OSI > 0.15 areas within the bifurcation region are more susceptible to atherosclerosis development. Full article

Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a high mortality rate upon rupture (85–90%). Surgical repair remains the most effective intervention, whereas pharmacological treatments to prevent aneurysm expansion or rupture are limited. Vascular smooth muscle cells (VSMCs) play a crucial role in AAA pathogenesis, and metabolic dysregulation is increasingly recognized as a contributor to disease progression. This study investigated metabolic changes in VSMCs and their association with AAA pathology using untargeted metabolomics. Methods: Angiotensin II (Ang II) was used to stimulate rat VSMCs and induce AAA in ApoE−/− mice. Untargeted metabolomic analysis was performed using liquid chromatography–tandem mass spectrometry to detect metabolite changes. Differential metabolites were identified using orthogonal partial least squares discriminant analysis, and metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes and metabolic set enrichment analysis. Results: In Ang II-treated VSMCs, 54 differential metabolites (24 upregulated; 30 downregulated) were identified, whereas 470 differential metabolites (206 upregulated; 264 downregulated) were detected in mouse aortas. Three metabolites—carnitine, lysophosphatidylcholine (0:0/20:4), and 5-hydroxyeicosatetraenoic acid—were common in both models and were enriched in bile secretion and tryptophan metabolism pathways. The carnitine–FXR signaling axis emerged as a potential therapeutic target. Conclusions: This study revealed Ang II-induced metabolic changes in VSMCs and their association with AAA pathology. The carnitine–FXR signaling axis may contribute to AAA development, providing new directions for diagnostic biomarkers and therapeutic targets. Future studies should validate these findings in human AAA samples to determine their clinical relevance. Full article

Background/Objectives: The menopausal decline in estrogen levels accelerates age-related changes, including visceral adiposity, insulin resistance, sarcopenia, osteoporosis, and endothelial dysfunction. While nutrition independently influences these outcomes, the interactive role of estrogen signaling and nutrient metabolism in healthy aging remains underexplored. This article evaluates these interactions. Methods: We conducted a narrative synthesis of studies examining estrogen’s effects on energy balance, adipose regulation, muscle, bone, and cardiovascular health, with an emphasis on estrogen-like nutritional modulators and phytoestrogens. In addition, we present original experimental data from our laboratory investigating sex-specific vascular responses to G protein-coupled estrogen receptor (GPER) activation using functional myography in isolated rat aortic rings from young adult and middle-aged rats (n = 6–8 per group) to assess responses to the GPER agonist G-1 (1.0 μM). Results: Literature evidence demonstrates that estrogen supports macronutrient utilization, suppresses adipose inflammation, preserves bone density, and promotes endothelial function. Phytoestrogens may engage estrogen-responsive pathways to mitigate age-related physiological decline. Our original findings show that GPER agonism enhances both contractile and vasodilatory responses in female (p < 0.05) but not male rat aortas, providing mechanistic evidence of sex-specific vascular estrogen signaling. These results suggest that dietary phytoestrogens and nutrient-rich dietary patterns may, in part, activate GPER-dependent pathways to support cardiovascular resilience in aging women. Conclusions: Estrogen–nutrition interactions are central to metabolic adaptation and healthy aging. Our findings highlight GPER as a functionally resilient pathway in aging vasculature, offering a putative mechanistic link for nutritional modulation. However, direct translation of these findings to human clinical outcomes remains to be established. Precision nutrition strategies targeting GPER represent a promising framework for healthy aging, though large-scale human trials are necessary to confirm these receptor-specific effects. Full article

Background/Objectives: Molecular hydrogen (H₂), a natural antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite without affecting signaling molecules such as H₂O₂ and NO. In addition, H₂ can inhibit the synthesis of inflammatory cytokines. Human and animal studies have shown that the inhalation of H₂ has a hypotensive effect. In this context, the aim of the present work was to study the effect of H₂ on the baroreflex regulation of blood pressure in rats with experimental monocrotaline-induced pulmonary hypertension (MCT) in vivo and the effects of H₂ on the reactivity of isolated rat aorta with MCT pulmonary hypertension to α₁-adrenoceptor agonists in vitro. Methods: Experiments were performed on male Wistar rats with MCT pulmonary hypertension; animals were placed in plastic chambers aerated with atmospheric air at a rate of 4 L/min with O₂ and CO₂ control. Cages with the rats of the MCT-H₂ and Control-H₂ groups were ventilated with air containing 4% H₂ twice daily for 2 h each. The MCT-Air and Control-Air groups breathed only atmospheric air. The duration of the experiment was 21 days. On day 20, blood pressure and heart rate (HR) were measured in awake animals and the baroreflex response to phenylephrine (PE) and nitroprusside (NP) was tested. In in vitro experiments, we studied the effect of adding H₂ to the perfusion solution on the responsiveness of isolated aortic preparations from MCT and control rats to the α₁-adrenoceptor agonist PE and the vasodilators NP and Acetylcholine. Results: When the effect of H₂ on the baroreflex response to NP (4.5 μg/kg) was examined in awake rats, the increase in HR was 73.1 ± 16.7 beats/min in the MCT-Air group and 48.1 ± 10.2 beats/min in the MCT-H₂ group (p < 0.01). In the Control-H₂ and Control-Air groups, there was a trend towards a lower HR in the Control-H₂ group, but the differences were not significant. No differences in HR response to PE administration were found between any of the experimental groups. Experiments on isolated aortic preparations from MCT rats showed that the addition of H₂ to the perfusion medium resulted in a 30% reduction in the maximal response to PE compared with the MCT group without hydrogen (p < 0.01), and the potency of PE (EC₅₀) decreased threefold (p < 0.05). There was a decrease in tryptase secretion, indicating an anti-inflammatory effect of H₂. Conclusions. The results demonstrate that H₂ inhalation was associated with an attenuated heart rate response to nitroprusside-induced hypotension and reduced vascular reactivity to phenylephrine in rats with pulmonary hypertension. Full article

Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light–dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4α (Hnf4a), newly implicating HNF4α as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders. Full article

Degraded mechanical properties in the aortic wall can lead to the formation of aortic aneurysms, potentially resulting in life-threatening ruptures. Current diagnostic criteria using maximum aortic diameter often fail to predict this critical moment, underscoring the need for more accurate patient-based prediction methods. A hospital-compatible experimental apparatus was designed for quasi-static ex vivo inflation testing of intact Ascending Thoracic Aortic Aneurysm (ATAA) specimens with 360° full-field three-dimensional digital image correlation (3D-DIC). Given hospital handling constraints, liquid pressurization was not feasible; instead, pressure was applied via a balloon-driven pneumatic system, and synchronized stereo imaging was used to measure surface displacement fields between 80 and 120 mmHg. The system was validated using a CT-derived ATAA silicone phantom. Full-field displacement measurements showed close agreement with finite element simulations, supporting the mechanical reliability of the apparatus and the repeatability of the measurement workflow. In addition, a frozen–thawed healthy porcine thoracic aorta was tested to demonstrate biological feasibility, particularly regarding the speckle application and DIC tracking, without aiming to extract tissue constitutive parameters. Overall, the setup provides a practical framework for acquiring full-field inflation-induced deformation data from intact aortic specimens in a hospital setting, enabling future studies on resected human ATAA tissue and model calibration that may contribute to more accurate methods for rupture prediction. Full article

Automated quality assurance is essential for low-dose computed tomography (LDCT) lung screening, yet manual checks strain clinical workflows. We present a fully automated artificial intelligence tool that quantifies scan coverage and image noise in LDCT without user input. Lungs and the aorta are segmented to measure cranial/caudal over- and underscanning, and noise is computed as the standard deviation of Hounsfield units (HUs) within descending aortic blood, normalized to a 1 ${\mathrm{mm}}^3$ voxel. Performance was verified in a reader study of 98 LDCT scans from the National Lung Screening Trial (NLST), and then applied to 38,834 NLST scans reconstructed with a standard kernel. In the reader study, lung masks were rated ≥“Nearly Perfect” in 90.8% and aorta-blood masks in 96.9% of cases. Across 38,834 scans, mean overscanning distances were 31.21 mm caudally and 14.54 mm cranially; underscanning occurred in 4.36% (caudal) and 0.89% (cranial). The tool enables objective, large-scale monitoring of LDCT quality—reducing routine manual workload through exception-based human oversight, flagging protocol deviations, and supporting cross-center benchmarking—and may facilitate dose optimization by reducing systematic over- and underscanning. Full article

This work focuses on the development of a patient-specific transient CFD–FSI numerical model combined with the Time-Averaged Entropy Generation Rate (TAEGR) to predict hemodynamic parameters in the thoracic aorta, including the Oscillatory Shear Index (OSI) and the Time-Averaged Wall Shear Stress (TAWSS). While arterial blood flow can be modeled assuming either rigid or elastic arterial walls, the effect of wall compliance on these parameters, particularly on TAEGR, remains insufficiently characterized. Moreover, the interpretation of established indicators is not unique, as regions of vascular relevance may correspond to either high or low values of OSI and TAWSS. The proposed approach aims to identify symmetry and asymmetry in shear stress and entropy generation within the arterial wall, which are closely associated with the development of atherosclerotic plaque. Four aortas from clinical patients were analyzed using the proposed numerical framework to investigate blood flow behavior. The results revealed regions with high values of the hemodynamic parameters (OSI > 0.15, TAWSS ≥ 2 Pa, and TAEGR ≥ 20 $\mathrm{W}/{\mathrm{m}}^3\mathrm{K}$) predominantly located in the vicinity of the upper arterial branches. These regions, referred to as critical zones, are considered prone to the development of cardiovascular diseases, particularly atherosclerosis. The proposed numerical model provides a reliable qualitative framework for assessing symmetry and asymmetry in aortic blood flow patterns under different surgical conditions. Full article

Current pharmacotherapies against atherosclerotic cardiovascular disease are associated with considerable residual risk, together with various adverse side effects. Nutraceuticals, such as resveratrol (RSV), with excellent safety profile, represent promising alternatives and potential treatment. However, the full spectrum of anti-atherogenic actions regulated by RSV and the underlying molecular mechanisms remain poorly understood. The objective of this study therefore was to investigate the impact of RSV on key atherosclerosis-associated processes in monocytes, macrophages, endothelial cells, and smooth muscle cells in vitro, as well as in LDL receptor-deficient mice fed a high-fat diet in vivo. RSV produced beneficial changes in the plasma lipid profile and peripheral blood lymphoid cells in vivo. RSV also attenuated plaque inflammation by decreasing macrophage and T cell content and enhanced markers of plaque stability, with increased levels of smooth muscle cells and collagen content. In vitro, RSV inhibited chemokine-driven monocyte migration, inflammasome activation, matrix metalloproteinase activity, pro-inflammatory gene expression, reactive oxygen species production, and smooth muscle cell invasion. RNA-sequencing of the thoracic aorta revealed key genes and pathways mediating the antioxidant, anti-inflammatory and plaque-stabilising activities of RSV. These studies provide novel mechanistic insights on the anti-atherogenic actions of RSV and support further evaluation in human clinical trials. Full article

Cardiovascular diseases are a major cause of morbidity and mortality in chronic kidney disease (CKD) patients. Integrin-linked kinase (ILK) regulates integrin–extracellular matrix interactions and vascular integrity. This study investigated the role of ILK in CKD-associated vascular alterations. An adenine-supplemented diet induced a progressive CKD in wild-type (WT) and conditional ILK knock-down (cKD-ILK) mice. Aortic tissue was collected for histology and RT-qPCR analysis. Moreover, aortas were incubated ex vivo with the uremic toxins p-cresyl sulfate and indoxyl sulfate. In vitro, human aortic vascular smooth muscle cells were exposed to uremic toxins, and the effect of siRNA-mediated ILK silencing was tested. Aortas of adenine-fed WT mice showed a progressive increase in ILK expression, morphological alterations, and increased fibrosis, which was not observed in cKD-ILK aortas, compared to control mice. Statistically significant correlations between vascular content of ILK and fibrosis markers were observed. Ex vivo, uremic toxins increased ILK and fibrosis protein expression in WT aortas but not in cKD-ILK. In vitro, uremic toxins increased ILK activity and fibrosis markers, like collagen, while ILK-deleted cells prevented collagen increase. ILK depletion prevents CKD-associated vascular fibrosis, suggesting ILK as a potential therapeutic target to prevent arterial alterations in renal patients. Full article

Background: Animal models are essential for translating diagnostic and therapeutic strategies into clinical practice and offer valuable insights into the pathophysiology of diseases such as aortic dissection. This study presents a novel acute in vivo large animal model of Stanford type A aortic dissection, combining open surgical access with endovascular techniques to leverage the advantages of both. The model aims to reproducibly simulate acute dissections in swine, providing a standardized platform for evaluating diagnostics, disease mechanisms, and treatment strategies. Methods: Six pigs underwent a standardized protocol to induce aortic dissection. Arterial pressure was monitored via femoral and carotid catheterization. A conventional sternotomy was performed, followed by tangential cross-clamping of the ascending aorta and a controlled incision proximal to the brachiocephalic trunk. The intima and the media were separated using a guidewire and catheter-based technique to create a false lumen. A re-entry tear was also established to allow for controlled intraluminal access. Animals were monitored for 12 h post-intervention, with serial blood sampling. At the end of the experiment, the animals were euthanized and the aortas harvested for macroscopic and histological analysis. Results: In all 6 animals, the placement of arterial catheters in femoral and carotid arteries, as well as the sternotomy, was established without any complications. The dissection model was successfully created in 5 out of 6 animals by clinical signs such as adventitial hematoma, macroscopic wall separation and/or decreased femoral blood pressure. One animal experienced complete aortic perforation. Five animals completed the full observation period of 12 h. Conclusion: A standardized, reproducible, and robust large animal model of acute Stanford type A aortic dissection using a hybrid approach was developed. This model closely simulates the clinical and pathological features of human aortic dissection, making it a valuable tool for preclinical research in diagnostics, pathophysiology, and treatment development. Full article

Citri grandis exocarpium (Citri grandis) has been consumed by human beings for fifteen hundred years. It is commonly consumed as a health drink and dietary supplement in China. However, its nutritional and healthcare functions are still not fully understood. Objective: Our previous study found that oral administration of Citri grandis extract can significantly decrease the blood lipid levels of hyperlipidemic mice fed a high-fat diet. The aim of this study was to confirm the preventative effects of Citri grandis extract against atherosclerosis. Methods: Atherosclerotic lesion models were induced in HUVECs and apoE^−/− C57BL/6J mice. ApoE^−/− mice fed a high-fat diet were orally administered Citri grandis extract (0.4, 0.8, and 1.6 g/kg/d BW) and Simvastatin (1 mg/kg/d BW) on the first day of model establishment. After a 16-week treatment, serum samples and aorta and liver tissues were collected. Observation of pathological changes in aortic and liver tissues was performed using a light microscope with oil red O, H&E, Masson’s trichrome staining, and TEM. Biochemical detection was employed to determine the serum levels of TC, TG, LDL-C, and HDL-C as well as the activities of AST and ALT. In addition, expression studies of TGF-β, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1 were performed via qPCR and Western blot analysis. Results: Compared with cholesterol-induced HUVECs, Citri grandis extract significantly enhanced cell viability, attenuated the morphological changes in HUVECs, and reduced LDH release. Furthermore, after treatment with Citri grandis extract, the levels of TC, TG, and LDL-C significantly decreased in the atherosclerosis model apoE^−/− mice after 16 weeks, and aortic plaque, lipid deposition, and endothelial injury were obviously ameliorated. The mRNA and protein expression of TGF-β, PPAR-γ, LXR-α, and ABCA1 in aortic and liver of atherosclerosis apoE^−/− mice were upregulated (p < 0.05, p < 0.01), while those of PI3K and Akt1 were suppressed (p < 0.05, p < 0.01). Conclusions: Citri grandis extract can significantly decrease the high circulating lipid levels and the liver lipid deposition of high-fat-diet-fed apoE^−/− mice and reduce aorta lipid accumulation and atherosclerotic plaques by regulating the expression of TGF-β1, PI3K, AKT1, PPAR-γ, LXR-α, and ABCA1. Citri grandis extract can be used as a healthcare dietary supplement for the prevention of abnormal lipid metabolism and atherosclerosis. Full article