Search Results (353)

Background: Thoracic aortic aneurysm (TAA) is driven by complex molecular mechanisms beyond size thresholds, yet the role of cyclic nucleotide metabolism remains unclear. Phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP in compartmentalized microdomains, act as key regulators of vascular integrity and remodeling. Methods: We performed a hypothesis-driven, transcriptomic analysis of 20 PDE isoforms using the GSE26155 dataset (43 TAA vs. 43 controls). Raw microarray data underwent background correction, log2 transformation, and false-discovery adjustment. Differential expression, logistic regression, receiver-operating characteristic (ROC) curves, calibration testing, correlation analysis, and interactome/enrichment mapping were conducted. Results: Thirteen PDE isoforms were significantly dysregulated in TAA. Upregulated transcripts included PDE10A, PDE2A, PDE4B, PDE7A, and PDE8A, whereas PDE1A/B/C, PDE3B, PDE5A, PDE6C, and PDE8B were downregulated. PDE10A achieved excellent discrimination for TAA (AUC = 0.838), while other isoforms demonstrated fair discriminatory ability. Correlation architecture revealed coordinated regulation between PDE subfamilies, including inverse relationships between PDE2A and PDE8B (r = −0.68). Interactome analysis highlighted dense connections with cyclic nucleotide and purinergic signaling hubs, enriched in vascular tone, NO–cGMP–PKG, and junctional assembly pathways. Integrating these findings with epigenetic and junctional frameworks suggests that PDE dysregulation promotes endothelial barrier fragility and maladaptive smooth-muscle remodeling. Conclusions: Family-wide PDE dysregulation characterizes human TAA, with PDE10A emerging as a central transcriptomic signature. Altered cAMP/cGMP microdomain signaling aligns with junctional failure and epigenetic control, supporting the potential of PDE isoforms as biomarkers and therapeutic targets. These results provide experimental evidence that cyclic nucleotide hydrolysis is re-wired in TAA, supporting PDE10A as a novel biomarker and therapeutic target that bridges molecular dysregulation with clinical risk stratification in thoracic aortic disease. Full article

Dynamic environmental changes significantly affect trace element balance and exposure to toxic metals, influencing vascular homeostasis. The endothelium, as a key regulator of vascular tone and inflammation, is highly sensitive to fluctuations in micronutrient and heavy metal concentrations. This review summarizes current evidence on the molecular mechanisms by which essential trace elements, such as zinc, selenium, copper, and magnesium, support endothelial function through antioxidant defense, nitric oxide regulation, and anti-inflammatory signaling. Conversely, exposure to heavy metals including cadmium, lead, mercury, and arsenic induces oxidative stress, disrupts nitric oxide bioavailability, and promotes endothelial dysfunction, accelerating the pathogenesis of many diseases. The paper examines how these alterations contribute to the development of major cardiovascular diseases and outlines preventive measures to reduce associated risks. Understanding these interactions is crucial for society’s health amid growing environmental challenges. Full article

Vascular endothelium balances antithrombotic and anti-inflammatory activity to control blood vessel tone under physiological conditions. However, endothelial dysfunction impairs these processes, causing a state that promotes clotting and inflammation. Eicosanoids are a major class of bioactive lipid mediators crucial for modulating endothelial and platelet function. Research has highlighted the roles of eicosanoids in vascular diseases, showing pro-inflammatory, prothrombotic, and protective activities. Specifically, prostaglandin E₂ (PGE₂) is crucial because of its major role in atherosclerosis development and progression, acting via EP receptors involved in forming, maintaining, and stabilizing atherosclerotic lesions, thereby making PGE₂-EP signalling a specific target for treating cardiovascular diseases. This review will explore the evidence on eicosanoids and the role of their receptor modulation in platelet and vascular dysfunction in atherothrombosis. The studies included in this scoping review were retrieved from PubMed, Web of Science, Cochrane, and Scopus in accordance with the Preferred Reporting Items for Scoping Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) statement and the Population Intervention Comparison Outcome Population (PICO) framework. Eight clinical studies were found, which highlighted the crucial role of eicosanoids, like prostaglandins and their receptors, in endothelial and platelet dysfunction, and also how pharmacological mechanisms affect atherothrombosis. A new therapeutic approach for cardiovascular dysfunction is indicated by the recent findings, specifically against atherothrombosis, focusing on eicosanoids, their receptors, and processes like oxidative stress. Despite this evidence, there is a lack of comprehensive research results from scientific databases; therefore, further in vitro, in vivo, and clinical studies should be promoted to validate the preliminary results. Full article

Vascular Smooth Muscle Cells (VSMC) dysfunction is a major contributor to Type 1 diabetes (T1D)-associated vascular complications. Ca²⁺ is a key messenger responsible for maintaining VSMC tone and function, and alterations in its cytosolic levels are central to diabetes-related vasculopathy. Heat Shock Protein 70 (HSP70), a multifaceted chaperone present intracellularly (iHSP70), regulates vascular reactivity by supporting Ca²⁺ handling, and extracellularly (eHSP70) activates immune signaling. Disruption of eHSP70/iHSP70 balance has been implicated in T1D-associated VSMC dysfunction. Curcumin, a phytochemical found in turmeric, is an emerging therapeutic adjuvant for treating a wide range of pathologies, including diabetes. However, whether curcumin modulates Ca²⁺ dynamics and HSP70 expression, thereby improving VSMC function, in diabetic aorta remains unclear. To investigate this, Streptozotocin-induced diabetic rats (i.p. 65 mg/kg) were treated with curcumin (300 mg/kg) for 28 days. Vascular function was evaluated using wire myography to assess changes in biphasic contraction curve and Ca²⁺ dynamics, while HSP70 was quantified using Western blotting and ELISA. Structural alterations were analyzed by assessing collagen and elastin using Picrosirius staining and fluorescence microscopy. Chronic curcumin treatment improved vascular function by normalizing Ca²⁺ mishandling, restoring the eHSP70/iHSP70 ratio, reducing hypercontractility, and mitigating arterial structural alterations. These findings indicate that curcumin could potentially ameliorate diabetes-related VSMC dysfunction by restoring Ca²⁺ homeostasis and modulating HSP70. Full article

The liver is intricately innervated by sympathetic, parasympathetic, and sensory fibres, forming a dynamic neurovascular and neuroimmune network that regulates hepatic function and contributes to disease pathogenesis. While traditionally underexplored, hepatic innervation is now recognised as a key modulator of metabolic homeostasis, immune surveillance, and vascular tone. Historically, the liver was not considered a major target of neural regulation, but recent advances in neurology and imaging have revealed complex and dynamic interactions between neural circuits and hepatic functions. This review provides a comprehensive overview of liver innervation, detailing its anatomical organisation and functional roles in both physiological and pathological contexts. We investigate the role of liver innervation in shaping immune responses, particularly in the context of metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and autoimmune liver diseases, including autoimmune hepatitis and primary biliary cholangitis. Special attention is given to the neuroimmune crosstalk that governs inflammation, fibrosis, malignancy, and tissue remodelling. Furthermore, we examine how neural inputs influence hepatic blood flow, sinusoidal endothelial function, and portal hypertension, highlighting the interplay between neural and vascular systems. We highlight neuromodulatory approaches, including vagus nerve stimulation and other agents to modulate liver inflammation, vascular dysfunction, and immune dysregulation. Finally, we discuss emerging research models, including liver organoids, Artificial Intelligence-based digital twins and biomaterials as innovative platforms designed to study neural-liver interactions and test new therapeutic strategies. By integrating neuromorphology, immunology, and hepatology, this review aims to advance our understanding of liver innervation as a central player in hepatic health and disease and to identify novel targets for therapeutic intervention. Full article

The development of optical noninvasive methods for assessing the functional state of peripheral vessels, including the microcirculatory vascular bed, requires advances in modeling peripheral hemodynamics in order to interpret diagnostic data in terms of vascular tone, wall stiffness, and other related parameters. This study proposes a simple theoretical evaluation model of the dynamics of skin perfusion by blood during a functional test with brachial artery occlusion. As a development of conventional volume-chamber and pressure-volume approaches, this study introduces a problem-oriented three-chamber hemodynamic model of an arm, which allows simulating blood circulation during occlusion of major brachial veins and arteries. The model describes the Poiseuille flow of incompressible viscous blood in vessels with compliant walls, the lumen area of which is regulated by internal blood pressure and vascular tone. The initial diagnostic data for model validation were obtained in clinical trials with the use of the incoherent optical fluctuation flowmetry technique. Comparison of clinical and theoretical results revealed a fundamental qualitative agreement. In this field of medical diagnostics, for the first time, the dynamics of optical signals during the occlusion were successfully interpreted and substantiated as a response to changes in blood pressure and vascular tone in the microcirculatory system. Full article

Brain function is reliant upon maintaining a constant internal environment; however, the methods employed to maintain this environment have historically been viewed as largely passive in nature, relying on diffusion and vascular pulsations to create the conditions necessary for continued brain activity. This review seeks to provide an overview of current data suggesting that brain clearance is in fact an active process that is dependent upon both the current regulatory state of the brain and the presence of noradrenergic slow vasomotion, which is generated by rhythmic output from the locus coeruleus (LC). The LC-generated output has been found to influence the degree of contraction exhibited by pericytes, the geometric shape of astrocytic end-feet, and vascular tone, ultimately impacting the rate of exchange between cerebrospinal fluid (CSF), interstitial fluid (ISF), and the blood–brain barrier through aquaporin-4 (AQP4) channels. These LC-generated rhythmic changes are thought to provide the mechanical forces necessary for sustaining the metabolic clearance of waste products within the parenchyma. This review seeks to synthesize several recent studies which indicate that LC-generated vasomotion correlates with both the structure and progression of sleep states, neuronal oscillation patterns, and metabolic states, and that dysfunction of this LC-generated rhythm may contribute to pathological features associated with Alzheimer’s disease, Parkinson’s disease, and small-vessel disease. Understanding the mechanisms of clearance within the brain as a physiologically tunable system will allow researchers to view brain clearance as an adaptive neuro-modulatory function rather than merely as a passive event. Therefore, the focus of this review is on identifying the potential applications of advancements in the field of physiological imaging, molecular biomarkers, and neuro-modulatory or vascular-based therapies for early detection and therapeutic manipulation of clearance processes. Understanding these mechanisms will potentially lead to enhanced cognitive resilience and immune regulation, and promote healthy brain aging. Full article

Myofascial pain (MFP) is one of the most frequent temporomandibular disorders (TMDs), primarily affecting the masseter and temporalis muscles. Various treatment strategies have been developed, including trigger point injections (TrP) and nerve blocks. Among these, the twin block technique has recently emerged as a promising, minimally invasive approach for simultaneously anesthetizing the masseteric and anterior deep temporal nerves through a single extraoral injection. This review presents the anatomical considerations essential for the application of the twin block technique. The course, branching patterns, and relationships of the masseteric and deep temporal nerves with adjacent vascular structures are described based on the current anatomical literature. A comparison is also made of isolated nerve blocks and the twin block, highlighting procedural protocols, clinical advantages, and safety profiles. The anatomical proximity between the masseteric and deep temporal nerves supports the rationale for a single-puncture approach, which can effectively reduce muscle tone, inhibit nociceptive input, and silence multiple trigger points simultaneously. In addition to its therapeutic benefits, the twin block can serve as a diagnostic tool to differentiate muscular from joint or odontogenic pain. In conclusion, the twin block technique offers a precise and efficient method for managing masticatory myofascial pain, provided that detailed anatomical knowledge is applied to ensure procedural accuracy, a low incidence of adverse effects, and patient safety. Full article

Endothelial nitric oxide synthase (eNOS, NOS3) regulates steroidogenesis, redox signalling, and the vascular tone of the ovaries. Despite varying outcomes in previous studies, the prevalent NOS3 rs1799983 (Glu298Asp) polymorphism may influence endocrine function during controlled ovarian stimulation (COS). On the retrieval day, we assessed follicular-fluid hormones, day-3 hormones, and controlled ovarian stimulation (COS) outcomes (follicles, oocytes, MII oocytes, embryos) in 62 antagonist IVF/ICSI cycles classified by NOS3 genotype (GG/GT/TT). The outcomes for COS and early-cycle hormones were mostly consistent across all genotypes. A similar allele-dose pattern was seen for baseline oestradiol (GG < GT < TT), with heterozygous carriers displaying higher levels of follicular-fluid β-hCG relative to GG individuals. No changes were seen in follicle count, oocyte production, nuclear maturation, or embryo development. Baseline oestradiol and follicular β-hCG serve as the principal indications of the modest, context-dependent endocrine effects of the NOS3 rs1799983 polymorphism in antagonist cycles. To clarify the clinical significance of these intricate genotype-associated patterns, additional comprehensive, genotype-balanced investigations that include direct NO-pathway phenotyping are essential. Full article

The small GTPase RhoA and its downstream effector Rho-kinase (ROCK) have emerged as pivotal regulators of vascular smooth muscle cell (VSMC) contraction, endothelial function, and vascular remodeling. Activation of the RhoA/ROCK pathway enhances calcium (Ca²⁺) sensitivity by inhibiting myosin light chain phosphatase (MLCP), thereby promoting sustained vascular tone independent of intracellular Ca²⁺ levels. In endothelial cells (ECs), RhoA/ROCK signaling contributes to nitric oxide (NO) dysregulation, oxidative stress, cytoskeletal reorganization, and inflammatory activation. Cumulative evidence implicates this pathway in the development and progression of hypertension and other cardiovascular diseases, where maladaptive vascular remodeling, VSMC proliferation, and endothelial dysfunction drive increased vascular resistance. Translational studies have identified ROCK inhibitors and indirect modulators such as statins as promising therapeutic strategies. This review integrates recent mechanistic insights into RhoA/ROCK regulation of vascular function with clinical and translational perspectives on targeting this pathway in hypertension. Full article

The vascular endothelium serves as a critical barrier preventing the transmigration of monocytes, circulating lipoproteins, and other molecules into the subendothelial space, and plays a vital role in regulating vascular tone. A dysfunctional and inflamed endothelial layer in response to disturbed blood flow or other proatherogenic risk factors is the initiating event in the pathogenesis of atherosclerosis, suggesting the importance of an intact and properly functioning endothelium in preventing the onset and progression of this disease. Accumulated evidence demonstrates the significant role of matricellular proteins, which are non-structural and secretory extracellular matrix (ECM) proteins, in the development of atherosclerosis. These proteins exert multifaceted effects on endothelial cells (ECs) ranging from reactive oxygen species (ROS) production, endoplasmic reticulum stress, and expression of adhesion molecules to autophagy and compromised barrier function via stimulating various molecular mechanisms. Given the critical roles of these processes in EC function and atherosclerosis, a better understanding of signaling pathways governed by matricellular proteins in ECs is required to develop therapeutic strategies for suppressing or preventing atherosclerosis and related cardiovascular diseases (CVDs). This review comprehensively summarizes the existing literature on the diverse roles of matricellular proteins in regulating EC inflammation and function, and highlights their potential as viable therapeutic targets for maintaining vascular health and inhibiting the progression of atherosclerosis. Full article

The endothelium, once considered merely a vascular lining responsible for selective permeability to water and electrolytes, is now recognised as a key regulator of vascular tone through the release of mediators such as oxylipins, nitric oxide, and hyperpolarizing factors. This in vitro study investigated the biological activity of Vesvein, a natural formulation containing Diosmin/Hesperidin, Ruscus aculeatus, Bromelain, and Ananas comosus, on intestinal and endothelial cells. Vesvein enhanced intestinal cell viability and preserved barrier integrity, as demonstrated by increased tight junction expression at both single and double concentrations. In endothelial cells, the compound improved parameters linked to venous insufficiency, elevating nitric oxide production by approximately 1.39-fold at a single dose and 1.65-fold at a double dose. These findings indicate a potential role for Vesvein in supporting endothelial health and vascular function in vitro. Preliminary evidence from intestinal models further suggests preserved barrier properties, which may positively influence absorption and bioavailability, thereby enhancing its vascular benefits. Full article

Background/Objectives: Fluid management in shock remains a clinical challenge, with ongoing debate about optimal guidance. Despite advanced technologies, fluid balance assessment is often inadequate. The SkInShock study investigated whether transepidermal water loss (TEWL) measurements could improve fluid balance estimation and serve as a non-invasive marker of vascular tone in patients with septic or cardiogenic shock. Methods: In this prospective single-center feasibility study (DRKS00027981), TEWL was measured daily in eight mechanically ventilated patients using a Tewameter^® (Courage+Khazaka, Cologne, Germany), which quantifies transcutaneous water evaporation. Total daily skin water loss was calculated either via direct TEWL measurements or an estimation formula (6 mL/kg/day + 20%/°C deviation from 37 °C). Systemic vascular resistance index (SVRI) was measured simultaneously using PiCCO^® technology (Pulsion Medical Systems, Munich, Germany) to evaluate the relationship between TEWL and vascular tone. Results: TEWL values were consistent across most body sites, except the forehead. TEWL-based estimates of skin water loss were significantly lower than formula-based estimates (p < 0.01). Formula-based values overestimated water loss at low TEWL levels and underestimated it at higher levels, with deviations reaching ±100%. While absolute TEWL values did not correlate with SVRI, intra-individually normalized values showed a significant negative correlation, indicating that higher skin water loss corresponded to lower vascular tone. Conclusions: TEWL measurement is feasible in ICU patients and may enhance fluid balance assessment and vascular tone monitoring. Our preliminary findings indicate that this non-invasive method could complement current diagnostics but warrants further investigation in larger cohorts. Full article

Hydroxytyrosol (HXT), a phenolic compound from olive, shows great potential as a neuroprotective agent and a translational target for claim-ready nutrition and food products. Human studies increasingly report benefits for vascular function, inflammatory tone, and early cognitive/psychomotor outcomes, consistent with engagement of redox and signalling pathways (Keap1–Nrf2–ARE, PI3K/Akt–ERK, and AMPK–SIRT1–PGC-1α). HXT is rapidly absorbed and likely reaches the brain, acting on endothelial and microglial targets. On the neurovascular axis, it reduces oxidative stress, preserves nitric-oxide bioavailability, lower inflammatory markers, and favourable intrinsic connectivity. For product development, bitterness from oleuropein-rich inputs can be mitigated by hydrolysis, followed by structure-guided delivery to balance sensory quality with exposure. Viable formats include cyclodextrin inclusion, microencapsulation, and (micro)emulsions in lipid matrices, plus stability engineering for aqueous systems (acidification, chelation, low-oxygen handling, or barrier packaging). Matrix effects are consequential; some proteins and fibers may decrease HXT bioaccessibility, whereas lipid phases and microstructured carriers often enhance it. Clinically, recommended doses are ~7–15 mg/day chronically and ~30–60 mg acutely. As conclusions of this review, future work should prioritize harmonized pharmacokinetics–pharmacodynamics readouts, cognition anchored to a compact neurovascular/blood–brain barrier biomarker core, and head-to-head comparisons of manufacturable delivery formats. Full article

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent aminopeptidase that is found in several places and is thought to be a cytosolic enzyme that helps break down peptides. Recent studies, however, have revealed its extensive therapeutic relevance upon release into circulation, functioning not only as a biomarker for cellular injury but also as an active modulator of cardiovascular homeostasis and critical disease. High levels of circulating DPP3 (cDPP3) have been linked to the causes of cardiogenic shock, septic shock, acute coronary syndromes, heart failure, and serious viral diseases like COVID-19. Its enzymatic breakdown of angiotensin II disrupts vascular tone and myocardial contractility, leading to hemodynamic instability and multi-organ failure. In numerous cohorts, cDPP3 levels reliably correspond with disease severity, acute renal damage, and death, but dynamic trajectories yield superior predictive information relative to single assessments. In addition to risk stratification, translational studies utilizing rodent and porcine models illustrate that antibody-mediated inhibition of cDPP3 with the humanized monoclonal antibody Procizumab reinstates cardiac function, stabilizes renal perfusion, diminishes oxidative stress and inflammation, and enhances survival. First-in-human experiences in patients with refractory septic cardiomyopathy have further emphasized its therapeutic promise. DPP3 is a good example of a biomarker and a mediator in cardiovascular and critical care. Its growing clinical and translational profile makes cDPP3 a strong predictor of bad outcomes and a prospective target for treatment. Ongoing clinical trials using Procizumab will determine if neutralizing cDPP3 can lead to enhanced outcomes in individuals with cardiogenic and septic shock. This review outlines the physiological mechanisms, clinical implications, and emerging therapeutic potential of DPP3 in cardiovascular and critical care. Ongoing trials with Procizumab will clarify whether neutralizing cDPP3 can improve outcomes in patients with cardiogenic and septic shock. Full article