Vascular dementia is a highly heterogeneous neurodegenerative disorder induced by a variety of factors. Currently, there are no definitive treatments for the cognitive dysfunction associated with vascular dementia. However, early detection and preventive measures have proven effective in reducing the risk of onset and improving patient prognosis. Nitric oxide plays an integral role in various physiological and pathological processes within the central nervous system. In recent years, nitric oxide has been implicated in the regulation of synaptic plasticity and has emerged as a crucial factor in the pathophysiology of vascular dementia. At different stages of vascular dementia, nitric oxide levels and bioavailability undergo dynamic alterations, with a marked reduction in the later stages, which significantly contributes to the cognitive deficits associated with the disease. This review provides a comprehensive review of the emerging role of nitric oxide in the physiological and pathological processes underlying vascular dementia, focusing on its effects on synaptic dysfunction, neuroinflammation, oxidative stress, and blood‒brain barrier integrity. Furthermore, we suggest that targeting the nitric oxide soluble guanylate cyclase-cyclic guanosine monophosphate pathway through specific therapeutic strategies may offer a novel approach for treating vascular dementia, potentially improving both cognitive function and patient prognosis. The review contributes to a better understanding of the multifaceted role of nitric oxide in vascular dementia and to offering insights into future therapeutic interventions.

Hemorrhagic stroke (HS) is a neurological disorder caused by the rupture of cerebral blood vessels, resulting in blood seeping into the brain parenchyma and causing varying degrees of neurological impairment, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Current treatment methods mainly include hematoma evacuation surgery and conservative treatment. However, these methods have limited efficacy in enhancing neurological function and prognosis. The current challenge in treating HS lies in inhibiting the occurrence and progression of secondary brain damage after bleeding, which is a key factor affecting the prognosis of HS patients. Studies have shown that medical gas therapy is gaining more attention and has demonstrated various levels of neuroprotective effects on central nervous system disorders, such as hyperbaric oxygen, hydrogen sulfide, nitric oxide, carbon monoxide, and other inhalable gas molecules. These medical gas molecules primarily improve brain tissue damage and neurological dysfunction by regulating inflammation, oxidative stress, apoptosis, and other processes. However, many of these medical gasses also possess neurotoxic properties. Therefore, the use of medical gases in HS deserves further exploration and research. In this review, we will elucidate the therapeutic effects and study the advances in medical gas molecules in HS.

Basal forebrain cholinergic neurons (BFCNs) are the sole source of cholinergic innervation to the cerebral cortex and hippocampus in humans and the primary source in rodents. This system undergoes early degeneration in Alzheimer's disease. BFCNs terminal synapses are involved in the regulation of the cerebral blood flow by making classical synaptic contacts with other neurons. Additionally, they are located in proximity to cortical cerebral blood vessels, forming connections with various cell types of the neurovascular unit (NVU), including vascular smooth muscle cells, endothelial cells, and astrocytic end-feet. However, the effects of the BFCNs input on NVU components remain unresolved. To address this issue, we immunolesioned the nucleus basalis by administering bilateral stereotaxic injections of the cholinergic immunotoxin 192-IgG-Saporin in 2.5-month-old Wistar rats. Seven months post-lesion, we observed a significant reduction in cortical vesicular acetylcholine transporter-immunoreactive synapses. This was accompanied by changes in the diameter of cortical capillaries and precapillary arterioles, as well as lower levels of vascular endothelial growth factor A (VEGF-A). Additionally, the cholinergic immunolesion increased the density of cortical astrocytes and microglia in the cortex. At these post-BFCN-lesion stages, astrocytic end-feet exhibited an increased co-localization with arterioles. The number of microglia in the parietal cortex correlated with cholinergic loss and exhibited morphological changes indicative of an intermediate activation state. This was supported by decreased levels of proinflammatory mediators IFN-γ, IL-1β, and KC/GRO (CXCL1), and by increased expression of M2 markers SOCS3, IL4Rα, YM1, ARG1, and Fizz1. Our findings offer a novel insight: that the loss of nucleus basalis cholinergic input negatively impacts cortical blood vessels, NVU components, and microglia phenotype.

Functional sympatholysis, the blunting of sympathetic vasoconstriction during exercise, is critical for regulating exercise hyperemia. The role of cytochrome P450-2C9 (CYP450) pathways in functional sympatholysis remains unclear. A total of 21 participants (11 females) completed three study visits (2 experimental). Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (P > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, P < 0.001, d: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (P < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (P: 0.003, [Formula: see text]: 0.4) and their interaction (P: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, P: 0.001, r: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.NEW & NOTEWORTHY Evidence suggests that functional sympatholysis is an endothelial-dependent, nitric oxide and prostaglandin-independent process. We found that cytochrome P450-2C9 (CYP450-2C9) inhibition attenuated sympatholytic responses during dynamic handgrip exercise with superimposed lower body negative pressure. These data indicate that CYP450 pathways contribute to functional sympatholysis in young healthy humans.

Preeclampsia is a leading cause of maternal and fetal morbidity and mortality, with obesity recognised as a significant risk factor. However, the direct contribution of obesity to the pathophysiology underpinning preeclampsia remains unclear.

This study aimed to develop and characterise a diet-induced obese mouse model with superimposed preeclampsia to better understand the impact of obesity on disease pathogenesis.

Female mice were fed either standard rodent chow or a high-fat diet from weaning. At 8 weeks of age, mice were mated. Pregnant mice were treated with L-NG-Nitro arginine methyl ester (L-NAME; to block nitric oxide production) from gestational day (D)7.5 to D17.5 to induce a preeclampsia-like phenotype. Blood pressure was measured on D14.5 and D17.5, followed by the collection of maternal and fetal tissues for histological, biochemical, and molecular analyses.

Obese dams exhibited significantly increased body, fat pad, and liver weights compared to lean controls. While L-NAME induced hypertension in the control mice, contrary to expectations, the L-NAME-induced hypertension was partially attenuated in obese dams, with significantly lower systolic and diastolic blood pressures at D14.5 and reduced systolic pressure at D17.5. Fetal weights were comparable between groups, however, placentas were significantly heavier with obesity. Endothelial function, inflammatory markers, and renal gene expression patterns suggested distinct physiological adaptations in obese preeclamptic-like mice.

These findings challenge the prevailing assumption that obesity drives hypertension, endothelial dysfunction, and inflammatory markers. The differential vascular and physiological responses observed in the obese dams highlight the complexity of obesity-preeclampsia interactions and underscore the need for refined preclinical models to disentangle mechanistic contributions. This work has implications for personalised management strategies and targeted therapeutic interventions in obese pregnancies at risk of preeclampsia.

Aging is a major risk factor for cardiovascular disease, with hypertension being the most common outcome. Hypertension often stems from resistance arteries endothelial dysfunction. Recent research highlights the pivotal role of perivascular adipose tissue (PVAT) in regulating endothelial function. We hypothesized that PVAT senescence contributes to vascular dysfunction and hypertension during aging. We showed that naturally aged mice developed hypertension and elevated pro-inflammatory cytokines levels. Moreover, resistance mesenteric arteries showed impaired vascular relaxation that was normalized by apocynin, an antioxidant. The vascular dysfunction was endothelium- and PVAT-dependent, and marked by: decreased nitric oxide- and cyclooxygenase-dependent vascular relaxation, decreased expression of endothelial nitric oxide synthase, and increased cyclooxygenase 2 and NADPH oxidase subunits p22phox and gp91phox expressions in the endothelium and PVAT. Additionally, we observed that PVAT shows greater signs of senescence, particularly with higher p16 expression, indicating that PVAT is more prone to age-related cellular aging. Our findings suggest that in resistance mesenteric arteries PVAT-derived factors are crucial for triggering and amplifying vascular dysfunction in aging, leading to hypertension. The underlying mechanisms involve downregulation of endothelial nitric oxide synthase-derived nitric oxide, NADPH oxidase-dependent oxidative stress, and cyclooxygenase 2-derived vascular contractile factors. This research improves our understanding of the mechanisms behind age-related vascular dysfunction and associated hypertension and opens perspectives for targeted therapeutic strategies.

Microangiopathy is a key complication of diabetes, adversely effecting several organs including the heart, kidneys, eyes, and nerves. This review focuses on myocardial microvascular dysfunction, a condition characterized by altered vasomotion and long-term structural changes to coronary arterioles, resulting in impaired regulation of blood flow in response to varying oxygen demands of cardiomyocytes. Presence of myocardial microvascular dysfunction is associated with increased risk of cardiovascular disease, even in the absence of obstructive coronary artery disease. Several noninvasive imaging techniques to assess coronary physiology have significantly enhanced our understanding of the myocardial microcirculation. These methods allow for detailed visualization and quantification of blood flow, endothelial function, and inflammation in the microvasculature, providing critical insights into the early stages of microvascular disease in diabetes. A significant area of development is the use of advanced hybrid imaging techniques such as positron emission tomography/computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). The integration of advanced imaging technologies with artificial intelligence is also a key future direction. Overall, these advancements aim to improve the early detection and management of microvascular complications in diabetes, ultimately enhancing outcomes and quality of life. The aim of this review is to provide an overview of both established and emerging noninvasive imaging techniques for assessing myocardial microvascular dysfunction.

Platelet activation and adhesion on the surface of circulating tumor cells (CTCs) assist them in surviving within the vasculature and acquiring enhanced migratory potential. Simultaneously, protected by surrounding/covering "micro-thrombi," CTCs evade immune surveillance in circulation, thereby promoting hematogenous tumor metastasis. Based on this, we designed a self-assembling nanoenzyme drug GSNO@B (NO donor-modified GOx self-assembled with the hydrophobic drug BMS-202) against platelet-mediated tumor metastasis. This strategy involves the depletion of glucose by GOx, which inhibits platelets activity and reduces forming the micro-aggregation. Concurrently, the nanoenzyme in situ releases NO further diminishes the protective adhesion and micro-aggregation of platelet on the tumor cells surface, thereby exposing them in shear forces and immune recognition in the circulatory system. Concurrently, the disintegration of the nanoenzyme GSNO@B releases the immune checkpoint inhibitor BMS-202, further facilitating the immune clearance of CTCs. Therefore, through a three-step strategy, GSNO@B effectively suppresses primary tumors growth and metastatic tumors formation by blocking the platelet-mediated hematogenous tumor metastasis pathway.

The profession of a locomotive engineer involves stress, lack of adequate sleep and rest, and a sedentary lifestyle, all of which can contribute to the development of erectile dysfunction (ErD) as well as arterial hypertension.

Consecutive patients of the railway hospital in Barnaul with arterial hypertension aged 30-60 who work as machinists or assistant locomotive drivers were enrolled. Those who have symptoms of ErD were randomized into three groups: group 1 received an endogenous nitric oxide-synthase (NOS) activator, group 2 received a combination of endogenous NOS activator and phosphodiesterase type 5 inhibitor (PDE-5i), and group 3 received no additional treatment for ErD. 20 individuals belonged to the control group without ErD. A follow-up was conducted after 2 and 4 months.

A total of 85 individuals were examined (65 with symptoms of ErD). After 2 months of treatment, no significant changes in biomarkers and LDF (laser Doppler flowmetry) values were observed in groups 1 and 3. In group 2, ET-1 (endothelin-1) and hs-CRP (high-sensitivity C-reactive protein) returned to reference levels, and ischemic manifestations decreased. After 4 months, group 1 had increased mean blood flow and hs-CRP returned to reference levels. Group 2 showed improved microhemodynamics and biomarkers values. Group 2 patients had a higher IIEF and ICF total scores.

The combination of hypotensive drugs, PDE-5i, and NOS activator was the most effective method of treatment, improving hemodynamics and reparative properties of the endothelium by removing the substrate for thrombus formation. Treatment with an NO-synthase activator was shown to partially eliminate pathological processes in the endothelium.

Endothelial cells (ECs) are arranged side-by-side to create a semi-permeable monolayer, forming the inner lining of every blood vessel (micro and macrocirculation). Serving as the first barrier for circulating molecules and cells, ECs represent the main regulators of vascular homeostasis being able to respond to environmental changes, either physical or chemical signals, by producing several factors that regulate vascular tone and cellular adhesion. Healthy endothelium has anticoagulant properties that prevent the adhesion of leukocytes and platelets to the vessel walls, contributing to resistance to thrombus formation, and regulating inflammation, and vascular smooth muscle cell proliferation. Many risk factors of cardiovascular diseases (CVDs) promote the endothelial expression of chemokines, cytokines, and adhesion molecules. The resultant endothelial activation can lead to endothelial cell dysfunction (ECD). In vitro models of ECD allow the study of cellular and molecular mechanisms of disease and provide a research platform for screening potential therapeutic agents. Even though alternative models are available, such as animal models or ex vivo models, in vitro models offer higher experimental flexibility and reproducibility, making them a valuable tool for the understanding of pathophysiological mechanisms of several diseases, such as CVDs. Therefore, this review aims to synthesize the currently available in vitro models regarding ECD, emphasizing CVDs. This work will focus on 2D cell culture models (endothelial cell lines and primary ECs), 3D cell culture systems (scaffold-free and scaffold-based), and 3D cell culture models (such as organ-on-a-chip). We will dissect the role of external stimuli-chemical and mechanical-in triggering ECD.

Antioxidants had a growing interest owing to their protective roles in food and pharmaceutical products against oxidative deterioration and in the body and against oxidative stress-mediated pathological processes. Screening of antioxidant properties of plants and plant derived compounds requires appropriate methods, which address the mechanism of antioxidant activity and focus on the kinetics of the reactions including the antioxidants. Many studies have been conducted with evaluating antioxidant activity of various samples of research interest using by different methods in food and human health. These methods were classified methods described and discussed in this review. Methods based on inhibited autoxidation are the most suited for termination-enhancing antioxidants and, for chain-breaking antioxidants while different specific studies are needed for preventive antioxidants. For this purpose, the most commonly methods used in vitro determination of antioxidant capacity of food and pharmaceutical constituents are examined and also a selection of chemical testing methods is critically reviewed and highlighting. In addition, their advantages, disadvantages, limitations and usefulness were discussed and investigated for pure molecules and raw plant extracts. The effect and influence of the reaction medium on performance of antioxidants is also addressed. Hence, this overview provides a basis and rationale for developing standardized antioxidant capacity methods for the food, nutraceuticals, and dietary supplement industries. Also, the most important advantages and shortcomings of each method were detected and highlighted. The underlying chemical principles of these methods have been explained and thoroughly analyzed. The chemical principles of methods of 1,1-diphenyl-2-picrylhydrazyl (DPPH•) radical scavenging, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS·+) scavenging, ferric ions (Fe3+) reducing assay, ferric reducing antioxidant power (FRAP) assay, cupric ions (Cu2+) reducing power assay (Cuprac), Folin-Ciocalteu reducing capacity (FCR assay), superoxide radical anion (O2·-), hydroxyl radical (OH·) scavenging, peroxyl radical (ROO·) removing, hydrogen peroxide (H2O2) decomposing, singlet oxygen (1O2) quenching assay, nitric oxide radical (NO·) scavenging assay and chemiluminescence assay are overviewed and critically discussed. Also, the general antioxidant aspects of the main food and pharmaceutical components were discussed through several methods currently used for detecting antioxidant properties of these components. This review consists of two main sections. The first section is devoted to the main components in food and their pharmaceutical applications. The second general section includes definitions of the main antioxidant methods commonly used for determining the antioxidant activity of components. In addition, some chemical, mechanistic, and kinetic properties, as well as technical details of the above mentioned methods, are provided. The general antioxidant aspects of main food components have been discussed through various methods currently used to detect the antioxidant properties of these components.

Ultrasound-stimulated microbubbles cavitation (USMC) has been proved to improve tumor blood perfusion, which is closely related to the rise in nitric oxide (NO) bioavailability. This study was aimed to investigate whether the co-administration of USMC and NO signaling molecule could contribute to a further enhancement of tumor perfusion.

Ninety-six MC38 tumor-bearing mice were divided into eight groups to compare the efficacy of different NO-related molecules alone and in combination with USMC, including L-arginine (L-Arg), NOC-18 and sodium nitrite (SN). To better evaluate the changes of tumor perfusion, six mice in each group received contrast-enhanced ultrasound imaging and the other six received ultra-resolution microscopy before and after treatment. Differences in NO generation and tumor hypoxia after treatments were also compared to identify an ideal co-therapy strategy. Further, inhibitors of NO synthase and NO receptor were adopted to explore mechanisms of the co-therapy in improving tumor perfusion.

Contrast-enhanced ultrasound imaging and ultra-resolution microscopy showed that USMC and SN had a positive synergistic effect in improving tumor perfusion. NO synthase inhibitor failed to block this effect while NO receptor inhibitor did. The tumor perfusion enhancement accompanied with the alleviation of tumor hypoxia and the increase of NO production. L-Arg and NOC-18 did not demonstrate synergistic effects with USMC.

Co-administration of USMC and NO pathway is a promising modality to alleviate tumor hypoperfusion and hypoxia, among which SN is an effective reagent playing a positive synergistic effect with USMC.

Coronary artery spasm (CAS) is a reversible vasoconstriction of normal or atherosclerotic epicardial coronary arteries with a subsequent reduction in myocardial blood flow, leading to myocardial ischemia, myocardial infarction, severe arrhythmias, or even sudden death. It is an entity that should be recognized based on a particular clinical presentation. Numerous differences exist between CAS and obstructive coronary disease in terms of mechanisms, risk factors, and therapeutic solutions. The gold standard for CAS diagnosis is represented by transitory and reversible occlusion of the coronary arteries at spasm provocation test, which consists of an intracoronary administration of Ach, ergonovine, or methylergonovine during angiography. The pathophysiology of CAS is not fully understood. However, the core of CAS is represented by vascular smooth muscle cell contraction, with a circadian pattern. The initiating event of this contraction may be represented by endothelial dysfunction, inflammation, or autonomic nervous system unbalance. Our study explores the intricate balance of these factors and their clinical relevance in the management of CAS.

Pulmonary hypertension is a life-threatening condition characterized by elevated mean pulmonary arterial pressure and vascular resistance. Significant advances in diagnosis and treatment have been achieved over the 20th and 21st centuries, yet challenges remain in improving long-term outcomes.

This review discusses the historical milestones in understanding and pharmacotherapy of the pulmonary arterial hypertension (PAH). A comprehensive literature search was conducted to explore the earliest reports of each approved medication for pulmonary hypertension, along with historical papers detailing the pathophysiological and diagnostic development. Additionally, the search aimed to identify novel therapeutic strategies, including repositioned drugs and emerging targets.

While current therapies, such as prostacyclin analogs and PDE5 inhibitors, improve functional capacity and hemodynamics, they face limitations, including costs, administration, and a predominantly vasodilatory approach. Additionally, the limitations of current clinical trial designs for rare diseases like pulmonary arterial hypertension hinder the evaluation of potentially effective drugs. These challenges underscore the urgent need for translational research to optimize trial methodologies, accelerating the development of new therapies. Innovative approaches, such as drug repositioning and the exploration of novel molecular targets, are critical to overcoming these barriers and ensuring timely, effective, and affordable treatment options for patients with PAH.

Replicating the contractile function of arterial tissues in vitro requires precise control of cell alignment within 3D structures, a challenge that existing bioprinting techniques struggle to meet. In this study, we introduce the voxel-based embedded construction for tailored orientational replication (VECTOR) method, a voxel-based approach that controls cellular orientation and collective behavior within bioprinted filaments. By fine-tuning voxel vector magnitude and using an omnidirectional printing trajectory, we achieve structural mimicry at both the macroscale and the cellular alignment level. This dual-scale approach enhances vascular smooth muscle cell (VSMC) function by regulating contractile and synthetic pathways. The VECTOR method facilitates the construction of 3D arterial structures that closely replicate natural coronary architectures, significantly improving contractility and metabolic function. Moreover, the resulting multilayered arterial models (AMs) exhibit precise responses to pharmacological stimuli, similar to native arteries. This work highlights the critical role of structural mimicry in tissue functionality and advances the replication of complex tissues in vitro.

FLASH radiotherapy is a novel irradiation modality that employs ultra-high mean dose rates exceeding 40-150 Gy/s, far surpassing the typical ~0.03 Gy/s used in conventional radiotherapy. This advanced technology delivers high doses of radiation within milliseconds, effectively targeting tumors while minimizing damage to the surrounding healthy tissues. However, the precise mechanism that differentiates responses between tumor and normal tissues is not yet understood. This study primarily examines the ROD hypothesis, which posits that oxygen undergoes transient radiolytic depletion following a radiation pulse. We developed a computational model to investigate the effects of dose rate on radiolysis in an aqueous environment that mimics a confined cellular space subjected to instantaneous pulses of energetic protons. This study employed the multi-track chemistry Monte Carlo simulation code, IONLYS-IRT, which has been optimized to model this radiolysis in a homogeneous and aerated medium. This medium is composed primarily of water, alongside carbon-based biological molecules (RH), radiation-induced bio-radicals (R●), glutathione (GSH), ascorbate (AH-), nitric oxide (●NO), and α-tocopherol (TOH). Our model closely monitors the temporal variations in these components, specifically focusing on oxygen consumption, from the initial picoseconds to one second after exposure. Simulations reveal that cellular oxygen is transiently depleted primarily through its reaction with R● radicals, consistent with prior research, but also with glutathione disulfide radical anions (GSSG●-) in roughly equal proportions. Notably, we show that, contrary to some reports, the peroxyl radicals (ROO●) formed are not neutralized by recombination reactions. Instead, these radicals are rapidly neutralized by antioxidants present in irradiated cells, with AH- and ●NO proving to be the most effective in preventing the propagation of harmful peroxidation chain reactions. Moreover, our model identifies a critical dose rate threshold below which the FLASH effect, as predicted by the ROD hypothesis, cannot fully manifest. By comparing our findings with existing experimental data, we determine that the ROD hypothesis alone cannot entirely explain the observed FLASH effect. Our findings indicate that antioxidants might significantly contribute to the FLASH effect by mitigating radiation-induced cellular damage and, in turn, enhancing cellular radioprotection. Additionally, our model lends support to the hypothesis that transient oxygen depletion may partially contribute to the FLASH effect observed in radiotherapy. However, our findings indicate that this mechanism alone is insufficient to fully explain the phenomenon, suggesting the involvement of additional mechanisms or factors and warranting further investigation.

Hypertension is a serious health problems and a leading cause of adult mortality worldwide. Foeniculum. vulgare Mill, a plant traditionally used for various ailments, including cardiovascular disorders such as hypertension.

The objective of the study is to verify the vasorelaxant effect of fennel seeds on the isolated and perfused mesenteric vascular beds in rats.

The vasorelaxant effect of the aqueous extract of F. vulgare (AEFv) seeds was tested on mesenteric arteries, both intact and denuded, precontracted with phenylephrine. Extracts from liquid-liquid extraction of F. vulgare were screened to find the active fraction. The mechanism of action of the active butanolic fraction (BFFv) was studied using inhibitors like L-NAME (nitric oxide synthase inhibitor), ODQ (guanylate cyclase inhibitor), indomethacin (cyclooxygenase inhibitor), potassium channel blockers (tetraethylammonium TEA, and glibenclamide), and atropine (a muscarinic receptor antagonist). Moreover, the antioxidant properties of AEFv and BFFv were evaluated using DPPH radical scavenging, β-carotene linoleic acid, and ferric-reducing power assays; total flavonoids and phenolics of AEFv and BFFv were measured using Folin-Ciocalteu and aluminum chloride colorimetric assays; HPLC-DAD analysis and acute toxicity of BFFv in mice were also performed.

AEFv caused a concentration-dependent vasodilatory response in intact mesenteric arteries (Emax = 81.73 ± 0.36 %). This effect was significantly reduced after endothelium removal. The butanolic fraction showed the highest vasorelaxant effect. The vasodilatory effect was attenuated by L-NAME, ODQ, indomethacin, TEA, glibenclamide, and atropine, indicating involvement of the NO/GMPc pathway, potassium channels, and muscarinic receptors. Additionally, fennel extracts demonstrated excellent antioxidant activity and high concentrations of flavonoids and phenolic compounds. HPLC-DAD analysis of the butanolic fraction revealed an abundance of phenolic acids. Acute toxicity studies of BFFv showed no toxic effects.

Our findings support the traditional use of Foeniculum vulgare seeds for preventing cardiovascular disorders associated with vascular dysfunction, highlighting their vasorelaxant and antioxidant properties.

Adequate venous dilation is important for successful venipuncture and infusion insertion. While the warm compress method is commonly used, its mechanism remains unclear. This study investigated the impact of the warm compress method on blood nitric oxide (NO) concentration, known for its vasodilatory properties. Using a pre-and post-intervention design, participants underwent warm compress application on the non-dominant arm. The blood NO concentration, vein cross-sectional area, and skin temperature were measured pre-and post-intervention. A warm compress was applied at 39 °C to 42 °C for 5 minutes. The skin temperature was measured pre-intervention and after applying pressure with a tourniquet; a vein cross-sectional area image was acquired using ultrasonography, and 2 mL blood was drawn to measure NO. Post-intervention, skin temperature was measured, vein cross-sectional area images were obtained, and blood was similarly collected. Data were analyzed using the Wilcoxon signed-rank sum test. Among the 19 participants (7 men and 12 women; mean age: 42.6 ± 7.5 years), significant differences were observed in skin temperature (32.05 °C versus 39.40 °C), vein cross-sectional area (11.4 mm versus 14.8 mm2), and blood NO concentration (12.45 µmol/L and 11.18 µmol/L) pre- and post-intervention, possibly because the action of blood NO on vascular smooth muscle cells was promoted, leading to blood NO consumption.

Vascular endothelium is integral to the regulation of vascular homeostasis and maintenance of normal arterial function in healthy individuals. Endothelial dysfunction is a significant contributor to the advancement of atherosclerosis, which can precipitate cardiovascular complications. A notable correlation exists between diabetes and endothelial dysfunction, wherein chronic hyperglycemia and acute fluctuations in glucose levels exacerbate oxidative stress. This results in diminished nitric oxide synthesis and heightened production of endothelin-1, ultimately leading to endothelial impairment. In clinical settings, it is imperative to implement appropriate therapeutic strategies aimed at enhancing endothelial function to prevent and manage diabetes-associated vascular complications. Various antidiabetic agents, including insulin, GLP-1 receptor agonists, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, thiazolidinediones (TZDs), and metformin, are effective in mitigating blood glucose variability and improving insulin sensitivity by lowering postprandial glucose levels. Additionally, traditional Chinese medicinal compounds, such as turmeric extract, resveratrol, matrine alkaloids, tanshinone, puerarin, tanshinol, paeonol, astragaloside, berberine, and quercetin, exhibit hypoglycemic properties and enhance vascular function through diverse mechanisms. Consequently, larger randomized controlled trials involving both pharmacological and herbal interventions are essential to elucidate their impact on endothelial dysfunction in patients with diabetes. This article aims to explore a comprehensive approach to the treatment of diabetic endothelial dysfunction based on an understanding of its pathophysiology.

Following the COVID-19 pandemic, there are many chronically ill Long COVID (LC) patients with different symptoms of varying degrees of severity. The pathological pathways of LC remain unclear until recently and make identification of path mechanisms and exploration of therapeutic options an urgent challenge. There is an apparent relationship between LC symptoms and impaired cholinergic neurotransmission.

This paper reviews the current literature on the effects of blocked nicotinic acetylcholine receptors (nAChRs) on the main affected organ and cell systems and contrasts this with the unblocking effects of the alkaloid nicotine. In addition, mechanisms are presented that could explain the previously unexplained phenomenon of post-vaccination syndrome (PVS). The fact that not only SARS-CoV-2 but numerous other viruses can bind to nAChRs is discussed under the assumption that numerous other post-viral diseases and autoimmune diseases (ADs) may also be due to impaired cholinergic transmission. We also present a case report that demonstrates changes in cholinergic transmission, specifically, the availability of α4β2 nAChRs by using (-)-[18F]Flubatine whole-body positron emission tomography (PET) imaging of cholinergic dysfunction in a LC patient along with a significant neurological improvement before and after low-dose transcutaneous nicotine (LDTN) administration. Lastly, a descriptive analysis and evaluation were conducted on the results of a survey involving 231 users of LDTN.

A substantial body of research has emerged that offers a compelling explanation for the phenomenon of LC, suggesting that it can be plausibly explained because of impaired nAChR function in the human body. Following a ten-day course of transcutaneous nicotine administration, no enduring neuropathological manifestations were observed in the patient. This observation was accompanied by a significant increase in the number of free ligand binding sites (LBS) of nAChRs, as determined by (-)-[18F]Flubatine PET imaging. The analysis of the survey shows that the majority of patients (73.5%) report a significant improvement in the symptoms of their LC/MEF/CFS disease as a result of LDTN.

In conclusion, based on current knowledge, LDTN appears to be a promising and safe procedure to relieve LC symptoms with no expected long-term harm.

Hyperhomocysteinemia (HHcy) is associated with the development and progression of chronic cardiovascular diseases through the deleterious effects of high levels of homocysteine (Hcy) on the cardiovascular system. However, the exact mechanism of action of Hcy on the acute injury of the cardiovascular system following ischemia/reperfusion (I/R) remains unclear. The present study demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu2+ during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. In the present study, we utilized three cardiac I/R model: isolated rat heart, in vivo model as well as cell culture, and demonstrated that copper mobilization occurs during cardiac I/R, and the interactive toxic effect of Hcy and mobile Cu2+ during cardiac I/R induces necroptosis of cardiac microvascular endothelial cells (CMECs) and thus enhances cardiac dysfunction. Furthermore, we proved that the Cu2+ chelator TTM significantly mitigated the deleterious effects of Hcy and Cu2+ on CMECs and cardiac function both in vitro and in vivo. Mechanismly, the combinative effect of Hcy and Cu2+ are associated with the production of reactive oxygen species (ROS) and nitric oxide (NO) by NADPH oxidase (NOX) and endothelial nitric oxide synthase (eNOS), respectively. Subsequently, the overproduction of toxic peroxynitrite (ONOO-) induces CMECs necroptosis. The application of ROS scavengers in CMECs resulted in a notable reduction in necroptosis mediated by Hcy and Cu2+ under hypoxia/reperfusion (H/R) condition. These findings indicate that the mechanism by which Hcy and Cu2+ enhances cardiac dysfunction under I/R condition may be attributed to the stimulation of both NOX and eNOS activity, resulting in the generation of excessive ONOO- and subsequent necroptosis of CMECs.

Nitric oxide (NO) is a key signaling molecule involved in cellular communication and plays a critical role in various biological processes. Given its dual role in the pathogenesis of endometriosis, we conducted a systematic literature review to explore its mechanisms further. Numerous studies have investigated the expression and role of NO in various diseases, including those in the field of gynecology. However, the expression and role of NO in endometriosis remain a topic of ongoing debate. Therefore, we conducted a comprehensive literature review using the Cochrane Library, EMBASE, Google Scholar, PubMed, and SCOPUS databases to evaluate the induction and role of NO in the pathogenesis of endometriosis. Of the 27 papers ultimately reviewed, 22 (81.4%) reported that NO contributes to the pathogenesis of endometriosis, 3 (11.1%) suggested that NO acts as a protective mechanism against endometriosis, and 2 studies (7.4%) found no association between NO and the pathogenesis of endometriosis. The expression and levels of NO in endometriosis were associated with pregnancy, infertility, menstruation, and pelvic pain. Research conducted on rats and mice demonstrated that NO, nNOS, eNOS, and iNOS play significant roles in the development of endometriosis. Most studies suggested that increased NO levels are associated with the pathogenesis of endometriosis.

The escalating prevalence of tissue damage and its associated complications has elicited global apprehension. While nanomaterial-based wound healing exhibits significant potential in terms of curbing infections and surpassing conventional methods, unresolved concerns regarding nanomaterial controllability and precision remain unresolved, jeopardizing its practical applications. In recent years, a unique strategy for creating gas-releasing nanomaterials for wound repair has been proposed, involving the creation of gas-releasing nanomaterials to facilitate wound repair by generating gas donor moieties. The operational spatiotemporal responsiveness and broad-spectrum antibacterial properties of these gases, combined with their inability to generate bacterial resistance like traditional antibiotics, establish their efficacy in addressing chronic non-healing wounds, specifically diabetic foot ulcers (DFUs). In this review, we delve into the intricacies of wound healing process, emphasizing the chemical design, functionality, bactericidal activity, and potential of gas-release materials, encompassing NO, CO, H2S, O2, CO2, and H2, for effective wound healing. Furthermore, we explore the advancements in synergistic therapy utilizing these gases, aiming to enhance our overall comprehension of this field. The insights gleaned from this review will undoubtedly aid researchers and developers in the creation of promising gas-releasing nanomaterials, thus propelling efficient wound healing in the future.

Reactive oxygen species (ROS) produced by mechanically stretching cardiomyocytes is a crucial mediator to increase contractile force in accordance with the Frank-Starling law. However, excessive ROS production leads to oxidative stress, contributing to myocardial atrophic remodeling and cellular damage. NADPH oxidase, the primary enzyme responsible for ROS production localized on the plasma membrane and organelle membranes, plays a key role in membrane-oriented ROS signaling. Two isoforms of NADPH oxidase, Nox2 (constitutive) and Nox4 (inducible), are predominantly expressed in cardiomyocytes, each playing unique roles in different contexts. Recent studies have revealed that Nox proteins form protein signaling complexes with transient receptor potential (TRP) channel proteins, amplifying ROS signaling in hearts. This review presents the putative mechanism of protein-protein interaction between TRP and Nox and their pathophysiological significance in hearts and discusses therapeutic strategies targeting TRP-Nox protein interactions for the treatment of heart failure.

A decrease in female sex hormone levels in the body impairs vascular endothelium functioning, leading to vascular dysfunction associated with certain diseases. Animal models of ovariectomy are commonly used to understand its effects on vascular (dys)function. Fourier-transform infrared (FTIR) spectroscopy is a technique capable of extracting detailed molecular information and, as such, has been applied to various biological analyses. This study evaluated systemic changes in the ovariectomy model using mid-infrared spectroscopy. Thirty-eight serum samples from adult Wistar rats were analyzed and divided into 18 in the control group (SHAM) and 20 in the ovariectomized group (OVX). Bilateral ovariectomy was performed, followed by euthanasia of the rats after 15 days. The spectral collection was performed using the Bruker Alpha II equipment (Bruker, Germany), preprocessed, and analyzed using unsupervised analysis methods [principal component analysis (PCA)] and supervised analysis methods [partial least-squares discriminant analysis (PLS-DA)] (MATLAB 2023). For the PCA model, combinations between principal components (PCs) 1 to 4 were performed. Nevertheless, none of the PC combinations allowed a clear distinction between the OVX and SHAM groups. The PLS-DA model exhibited 66% sensitivity, 80% specificity, a false positive rate of 20%, and a false negative rate of 33%. The F-score was 0.727 and the accuracy was 72.7%. However, the y-permutation test demonstrated that this result was random. These results indicate that there is no significant difference in the systemic profile of rats subjected to ovariectomy surgery for 15 days when analyzed using mid-infrared spectroscopy.

This paper describes the first use of conductive metal-organic frameworks as the active material in the electrochemical detection of nitric oxide in aqueous solution. Four hexahydroxytriphenylene (HHTP)-based MOFs linked with first-row transition metal nodes (M = Co, Ni, Cu, Zn) were compared as thin-film working electrodes for promoting oxidation of NO using voltammetric and amperometric techniques. Cu- and Ni-linked MOF analogs provided signal enhancement of 5- to 7-fold over a control glassy carbon electrode (SANO = 6.7 ± 1.2 and 5.7 ± 1.1 for Ni3(HHTP)2 and Cu3(HHTP)2, respectively) for detecting micromolar concentrations of NO. Zinc-based MOF electrodes offered more limited enhancement (SANO = 3.1 ± 0.5), while the cobalt-based MOF analog had intrinsic redox activity at potentials close to NO oxidation, which interfered with sensing. Combining MOFs with a conductive polymer improved electrode stability under repeated electrochemical scanning (14 ± 3% decrease in signal over 10 scans). The stabilized Ni3(HHTP)2@polymer-coated electrodes were able to detect NO at physiologically relevant concentrations (LOD = 9.0 ± 4.8 nM) in amperometric sensing experiments, and exhibited moderate selectivity against ascorbic acid and nitrite (log kj,NO = -1.3 ± 0.3 and -0.83 ± 0.68 for ascorbic acid and nitrite, respectively). This study demonstrates that layered, conductive 2D MOFs have promising applicability for NO detection in aqueous environments.

This comprehensive review aims to provide a thorough overview of the vital role that extracellular vesicles (EVs) play in endothelial dysfunction, particularly emphasizing how physiological factors-such as sex and aging-along with significant cardiovascular risk factors, influence this process. The review covers studies ranging from the first description of EVs in 1945 to contemporary insights into their biological roles in intercellular signaling and endothelial dysfunction. A comprehensive analysis of peer-reviewed articles and reviews indexed in the PubMed database was conducted to compile the information. Initially, Medical Subject Headings (MeSH) terms included keywords aimed at providing general knowledge about the role of EVs in the regulation of endothelial signaling, such as "extracellular vesicles", "endothelium", and "intercellular signaling". Subsequently, terms related to the pathophysiological implications of EV interactions with endothelial dysfunction and cardiovascular disease were added, including "cardiovascular disease", "sex", "aging", "atherosclerosis", "obesity", and "diabetes". Additionally, the potential applications of EVs in cardiovascular disease were explored using the MeSH terms "extracellular vesicles", "cardiovascular disease", "biomarker", and "therapeutic strategy". The results of this bibliographical review reveal that EVs have the capacity to induce various cellular responses within the cardiovascular system and play a significant role in the complex landscape of endothelial dysfunction and cardiovascular disease. The composition of the EV cargo is subject to modification by pathophysiological conditions such as sex, aging, and cardiovascular risk factors, which result in a complex regulatory influence on endothelial function and neighboring cells when released from a dysfunctional endothelium. Moreover, the data suggest that this field still requires further exploration, as EV biology is continuously evolving, presenting a dynamic and engaging area for research. A deeper understanding of the molecular cargo involved in EV-endothelium interactions could yield valuable biomarkers for monitoring cardiovascular disease progression and facilitate the development of innovative bioengineered therapeutic strategies to enhance patient outcomes.

The discovery of nitric oxide (NO) and the role of endothelial cells (ECs) in its production has revolutionized medicine. NO can be produced by isoforms of NO synthases (NOS), including the neuronal (nNOS), inducible (iNOS), and endothelial isoforms (eNOS), and via the non-classical nitrate-nitrite-NO pathway. In particular, endothelium-derived NO, produced by eNOS, is essential for cardiovascular health. Endothelium-derived NO activates soluble guanylate cyclase (sGC) in vascular smooth muscle cells (VSMCs), elevating cyclic GMP (cGMP), causing vasodilation. Over the past four decades, the importance of this pathway in cardiovascular health has fueled the search for strategies to enhance NO bioavailability and/or preserve the outcomes of NO's actions. Currently approved approaches operate in three directions: 1) providing exogenous NO, 2) promoting sGC activity, and 3) preventing degradation of cGMP by inhibiting phosphodiesterase 5 activity. Despite clear benefits, these approaches face challenges such as the development of nitrate tolerance and endothelial dysfunction. This highlights the need for sustainable options that promote endogenous NO production. This review will focus on strategies to promote endogenous NO production. A detailed review of the mechanisms regulating eNOS activity will be first provided, followed by a review of strategies to promote endogenous NO production based on the levels of available preclinical and clinical evidence, and perspectives on future possibilities.

Coronary microvascular disease (CMD) is defined as impaired coronary flow reserve (CFR) and/or increased microvascular resistance (MR) without significant epicardial coronary stenosis. This definition allows for discordant CFR and MR values within patients with CMD. The aim of this meta-analysis is to characterise the prognostic value and pathophysiological backgrounds of CFR and MR con-/discordance.

A systematic search (PROSPERO CRD42024573004) identified studies determining CFR and MR in patients without significant epicardial coronary artery disease. Patients were divided into four groups: (1) normal CFR and MR, (2) abnormal CFR and MR, (3) abnormal CFR with normal MR and (4) normal CFR with abnormal MR and analysed for all-cause mortality and major adverse cardiovascular events (MACE).

We identified four studies representing 2310 total participants. Group B had the highest MACE (OR: 3.23; 95% CI 1.95 to 5.36) and mortality rate (OR: 2.27; 95% CI 1.12 to 4.58) compared with group A. Group C, associated with female sex, showed significantly higher MACE (OR: 2.07; 95% CI 1.25 to 3.45) but not mortality (OR: 1.89; 95% CI 0.92 to 3.88) compared with group A. In group D, associated with high body mass index, MACE and mortality rates did not differ significantly from group A (OR: 1.19; 95% CI 0.67 to 2.11 and OR: 0.55; 95% CI 0.16 to 1.90, respectively).

Abnormal CFR and MR are associated with a high risk of MACE and death. Abnormal CFR and normal MR are associated with an increased MACE-but not death. MACE and mortality risk in discordantly normal CFR and abnormal MR are low. Our findings show the need for tailoring CFR and MR diagnostic thresholds to patient characteristics and raise questions about the presence of CMD in patients with abnormal MR with normal CFR.

Recent studies have found that a link between people with type 1 diabetes mellitus (T1DM) are at higher risk of morbidity as well as mortality from COVID-19 infection, indicating a need for vaccination. T1DM appears to impair innate and adaptive immunity. The overabundance of pro-inflammatory cytokines produced in COVID-19 illness that is severe and potentially fatal is known as a "cytokine storm." Numerous cohorts have revealed chronic inflammation as a key risk factor for unfavorable COVID-19 outcomes. TNF-α, interleukin (IL)-1a, IL-1, IL-2, IL-6, and other cytokines were found in higher concentrations in patients with T1DM. Even more importantly, oxidative stress contributes significantly to the severity and course of COVID- 19's significant role in the progression and severity of COVID-19 diseases. Severe glucose excursions, a defining characteristic of type 1 diabetes, are widely recognized for their potent role as mediating agents of oxidative stress via several routes, such as heightened production of advanced glycation end products (AGEs) and activation of protein kinase C (PKC). Furthermore, persistent endothelial dysfunction and hypercoagulation found in T1DM may impair microcirculation and endothelium, which could result in the development of various organ failure and acute breathing syndrome.

Coronary circulation plays an essential role in delivering oxygen and metabolic substrates to satisfy the considerable energy demand of the heart. This article reviews the history that led to the current understanding of coronary physiology, beginning with William Harvey's revolutionary discovery of systemic blood circulation in the 17th century, and extending through the 20th century when the major mechanisms regulating coronary blood flow (CBF) were elucidated: extravascular compressive forces, metabolic control, pressure-flow autoregulation, and neural pathways. Pivotal research studies providing evidence for each of these mechanisms are described, along with their clinical correlates. The authors describe the major role played by researchers in the 19th century, who formulated basic principles of hemodynamics, such as Poiseuille's law, which provided the conceptual foundation for experimental studies of CBF regulation. Targeted research studies in coronary physiology began in earnest around the turn of the 20th century. Despite reliance on crude experimental techniques, the pioneers in coronary physiology made groundbreaking discoveries upon which our current knowledge is predicated. Further advances in coronary physiology were facilitated by technological developments, including methods to measure phasic CBF and its regional distribution, and by biochemical discoveries, including endothelial vasoactive molecules and adrenergic receptor subtypes. The authors recognize the invaluable contribution made by basic scientists toward the understanding of CBF regulation, and the enormous impact that this fundamental information has had on improving clinical diagnosis, decision-making, and patient care.

Iontophoresis studies face challenges due to the unknown absolute drug dose delivered and the possible effect of the current used in drug delivery on the microvessels, known as current-induced vasodilation. This study aimed to investigate how various concentrations of acetylcholine (ACh), delivered through transdermal iontophoresis using repeated current pulses, impact the recovery profile of the microvascular response.

The study included fifteen healthy volunteers, and microvascular responses to five concentrations of iontophorised ACh (ranging from 0.0055 mM to 55 mM) and sterile water were assessed at six forearm skin sites using polarized reflectance spectroscopy. Iontophoresis at each concentration involved three consecutive pulses separated 8 recovery periods.

Current-induced responses were more pronounced for lower concentrations of ACh and for sterile water. With repeated pulses, lower concentrations of ACh exhibited a recovery profile more akin to higher concentrations.

Through repeated iontophoresis of ACh, microvascular responses exhibit variation based on the drug concentration and the number of pulses administered. These variations are likely attributed to changes in skin conductivity and permeability.

Persistent coronary endothelial dysfunction predicts future adverse events; however, performing multiple invasive endothelial function tests is difficult in actual clinical practice. This study examined the association between carotid plaque progression and persistent coronary endothelial dysfunction using serial assessments of the coronary vasomotor response to acetylcholine (ACh) in the infarct-related artery (IRA) among patients with ST-elevation acute myocardial infarction (STEMI). This study included 169 consecutive patients with a first STEMI due to the left anterior descending coronary artery (LAD) occlusion who underwent successful percutaneous coronary intervention. The vasomotor response to ACh in the LAD was measured within two weeks after acute myocardial infarction (AMI) (first test) and repeated at six months (second test) after AMI. Ultrasonography of the bilateral common carotid artery and internal carotid artery was performed during the acute phase, and the thickest intima-media thickness (IMT) of either artery was measured as the maximum IMT. After six months, the IMT at the site of maximal IMT was re-measured to determine the carotid plaque progression. Finally, 87 STEMI patients analyzed. At 6 months, 25 patients (28.7%) showed carotid plaque progression. In a multivariable analysis, carotid plaque progression was identified as an independent predictor of persistent coronary endothelial dysfunction, both in terms of coronary diameter response [odd ratio (OR) 3.22, 95% confidence interval (95% CI) 1.13-9.15, p = 0.03] and coronary flow response [OR 2.65, 95% CI 1.01-7.00, p = 0.04]. Independently, carotid plaque progression is linked to persistent endothelial dysfunction in the IRA among STEMI survivors.

The established diagnosis of coronary endothelial dysfunction (CED) is through the response to low-dose acetylcholine during invasive coronary function testing (CFT). Current diagnostic criteria encompass deficient epicardial vasodilation and/or insufficient increase in coronary blood flow (CBF) calculated from additional Doppler flow velocity measurements. The aim is to evaluate the diagnostic yield of using angiographic epicardial vasomotion and CBF as single criteria for diagnosing CED during CFT.

A total of 110 patients with angina and non-obstructive coronary arteries who underwent clinically indicated CFT were included. CED was defined as any reduction in epicardial diameter through quantitative coronary angiography and/or < 50 % increase in CBF compared to baseline after low-dose acetylcholine.

Based on current diagnostic criteria, 78 % of patients (N = 86/110) was diagnosed with CED. When only considering epicardial diameter, 24 % CED (N = 21/86) and 50 % severe CED diagnoses (N = 19/38) were missed. When only considering CBF, 27 % CED (N = 23/86) and 18 % severe CED diagnoses (N = 7/38) were missed. A similar diagnostic yield for CED detection was found for both parameters (OR: 0.913, 95 %CI 0.481-1.726, p = 0.763). The incidence of CFT diagnoses was comparable among all groups.

As single parameters, both epicardial diameter and CBF were ineffective in accurately diagnosing CED compared to the current diagnostic criteria. Combining both parameters is necessary to diagnose the complete spectrum of CED, as missed diagnoses of deficient CBF responses (e.g., microvascular CED) and epicardial vasomotion (e.g., epicardial CED) might occur when relying on these parameters as single diagnostic criteria for CED.

Maintaining good vascular health is a major component in healthy ageing as it reduces the risk of cardiovascular diseases. Endothelial dysfunction, in particular, is a key mechanism in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. Recently, endothelial senescence has emerged as a pivotal early event in age-related endothelial dysfunction. Endothelial function is characterized by an imbalance between the endothelial formation of vasoprotective mechanisms, including the formation of nitric oxide (NO) and endothelium-dependent hyperpolarization responses, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidases and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that natural products, in particular several polyphenol-rich foods, can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. In addition, some can even exert beneficial effects on endothelial senescence. Moreover, some of these products have been associated with the prevention and/or improvement of established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. Therefore, intake of certain natural products, such as dietary and plant-derived polyphenol-rich products, appears to be an attractive approach for a healthy vascular system in ageing.

Endothelial dysfunction is a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, diabetes, and aging. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors, including nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH), and vasocontracting factors, such as arachidonic acid-derived mediators generated by cyclooxygenases, and an increased level of oxidative stress. Recently, endothelial senescence was reported to be an early trigger of endothelial dysfunction. Preclinical studies indicate that polyphenol-rich food, including anthocyanin-rich products, can activate pathways promoting an increased formation of vasoprotective factors and can prevent the induction of endothelial dysfunction in endothelial cells and isolated blood vessels. Similarly, intake of anthocyanin-rich products has been associated with the prevention and/or the improvement of an endothelial dysfunction in several experimental models of cardiovascular diseases, including physiological aging. Moreover, clinical data indicate that polyphenol-rich and anthocyanin-rich products can improve endothelial function and vascular health in humans with cardiovascular diseases. The present review will discuss both experimental and clinical evidence indicating that several polyphenol-rich foods and natural products, and especially anthocyanin-rich products, can promote endothelial and vascular health, as well as the underlying mechanisms.

Peptide Lv is a small endogenous secretory peptide with ~40 amino acids and is highly conserved among certain several species. While it was first discovered that it augments L-type voltage-gated calcium channels (LTCCs) in neurons, thus it was named peptide "Lv", it can bind to vascular endothelial growth factor receptor 2 (VEGFR2) and has VEGF-like activities, including eliciting vasodilation and promoting angiogenesis. Not only does peptide Lv augment LTCCs in neurons and cardiomyocytes, but it also promotes the expression of intermediate-conductance KCa channels (KCa3.1) in vascular endothelial cells. Peptide Lv is upregulated in the retinas of patients with early proliferative diabetic retinopathy, a disease involving pathological angiogenesis. This review will provide an overview of peptide Lv, its known bioactivities in vitro and in vivo, and its clinical relevance, with a focus on its role in angiogenesis. As there is more about peptide Lv to be explored, this article serves as a foundation for possible future developments of peptide Lv-related therapeutics to treat or prevent diseases.

Nitric oxide synthases (NOS) are enzymes responsible for the cellular production of nitric oxide (NO), a highly reactive signaling molecule involved in important physiological and pathological processes. Given its remarkable capacity to diffuse across membranes, NO cannot be stored inside cells and thus requires multiple controlling mechanisms to regulate its biological functions. In particular, the regulation of endothelial nitric oxide synthase (eNOS) activity has been shown to be crucial in vascular homeostasis, primarily affecting cardiovascular disease and other pathophysiological processes of importance for human health. Among other factors, the subcellular localization of eNOS plays an important role in regulating its enzymatic activity and the bioavailability of NO. The aim of this review is to summarize pioneering studies and more recent publications, unveiling some of the factors that influence the subcellular compartmentalization of eNOS and discussing their functional implications in health and disease.

Endothelial dysfunction is a strong prognostic factor in predicting the development of cardiovascular diseases. Dysfunctional endothelium loses its homeostatic ability to regulate vascular tone and prevent overactivation of inflammation, leading to vascular dysfunction. These functions are critical for vascular homeostasis and arterial pressure control, the disruption of which may lead to hypertension. Hypertension itself can also cause endothelial dysfunction, as endothelial cells are susceptible to haemodynamic changes. Although it is unclear which of those factors appear first, they create a vicious circle further damaging multiple organs, including the heart and vessels. There are also sex-specific differences in homeostatic functions of the endothelium regarding vessel tone regulation, which may contribute to differences in arterial blood pressure between men and women. Even more importantly, there are sex-differences in the development of endothelial dysfunction and vessel remodelling. Hence, an understanding of the mechanisms of endothelial dysfunction and its contribution to pathological vascular remodelling during hypertension is of critical importance. This review addresses immunological and metabolic aspects in mechanisms of endothelial dysfunction and the resulting mechanisms in vascular remodelling with respect to arterial hypertension, including the potential role of sex-specific differences.

Alzheimer's disease (AD), the most prevalent cause of dementia, is a progressive neurodegenerative condition that commences subtly and inexorably worsens over time. Despite considerable research, a specific drug that can fully cure or effectively halt the progression of AD remains elusive. Nitric oxide (NO), a crucial signaling molecule in the nervous system, is intimately associated with hallmark pathological changes in AD, such as amyloid-beta deposition and tau phosphorylation. Several therapeutic strategies for AD operate through the nitric oxide synthase/NO system. However, the potential neurotoxicity of NO introduces an element of controversy regarding its therapeutic utility in AD. This review focuses on research findings concerning NO's role in experimental AD and its underlying mechanisms. Furthermore, we have proposed directions for future research based on our current comprehension of this critical area.

Vascular function is impaired by conditions such as hypertension, dyslipidemia, and diabetes as well as coronary risk factors including age, smoking, obesity, menopause and physical inactivity. Measurement of vascular function is useful not only for assessment of atherosclerosis itself but also in many other aspects such as understanding the pathophysiology, assessing treatment efficacy, and predicting prognosis of cardiovascular events. It is therefore important to accurately assess the extent of vascular function. A variety of vascular function assessments are currently used in clinical practice, including flow-mediated vasodilation, reactive hyperemia index, strain-gauge pulse plethysmographs, pulse wave velocity, augmentation index, intima media thickness, and chemical biomarkers. However, it is also true that there is no gold standard method for measuring vascular function in humans. To use vascular function effectively, it is necessary to understand the measurement-related pitfalls.

6-Nitrodopamine (6-ND) is the predominant catecholamine released from isolated vascular tissues in both mammals and reptiles, with its release being significantly reduced by the NO synthesis inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME). The vasorelaxation induced by 6-ND is unaffected by either L-NAME or the soluble guanylate cyclase (sGC) inhibitor, ODQ, indicating an alternative mechanism of action. The vasorelaxant effect appears to be mediated through selective antagonism of dopamine D2 receptors rather than traditional nitric oxide (NO)-mediated pathways. This study examined the basal release of 6-ND, dopamine, noradrenaline, and adrenaline from the rabbit thoracic aorta by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Additionally, the effects of 6-ND and the dopamine receptor antagonist L741,626 on relaxation responses and electric-field stimulation (EFS)-induced contractions in aortic rings were assessed. Nitric oxide pathway inhibitors, including L-NAME, ODQ, and methylene blue, were utilized to assess the involvement of this pathway in 6-ND-induced vasorelaxation. Concentration-response curves for norepinephrine, epinephrine, and dopamine were generated in the presence and absence of 6-ND and L-741,626. The rabbit isolated aorta presented the basal release of endothelium-derived dopamine and 6-ND. Furthermore, 6-nitrodopamine and L-741,626 induced concentration-dependent relaxations in endothelin-1 pre-contracted aortic rings. The relaxations were reduced by the mechanical removal of the endothelium but unaffected by pre-treatment with L-NAME, ODQ, or methylene blue. Pre-incubation with 6-ND significantly reduced dopamine-induced contractions, while noradrenaline- and adrenaline-induced contractions remained unchanged. The findings demonstrated that endothelium-derived 6-ND is the most potent endogenous relaxant of the rabbit isolated aorta, and the mechanism is independent of the NO pathway and involved the blockade of dopamine D2 receptors.

This study investigates the dose-response relationship of acetylcholine (ACh) on healthy human gingival blood flow (GBF). Understanding this dose-response relationship contributes to studying vasodilatory mechanisms in various pathological conditions.

The study involved 22 young healthy men (21 - 32 years) to investigate the dose-response relationship of ACh on GBF. Semi-circular wells were created on the labial surface of the upper right second incisor (FDI #12) and upper left first incisor (FDI #21), including the gingival sulcus, for the application of drugs. ACh-chloride solutions at 0.1, 1, and 10 mg/mL were administered to the gingival sulcus of tooth FDI #12 with a Hamilton syringe. Physiological saline was applied on the contralateral side to FDI #21 as a control. The GBF was measured non-invasively by the laser speckle contrast imaging method in four 1mm high adjacent regions: coronal, midway1, midway2, and apical, and was expressed in a laser speckle perfusion unit (LSPU). After the baseline blood flow recording, ACh doses were applied sequentially, with washout periods in between. Data were statistically analyzed using a linear mixed model.

The GBF did not change on the saline site throughout the experiment. The GBF was significantly higher at the coronal region after all ACh doses (baseline: 218±31 LSPU, and 227±38 LSPU p < 0.05, 239±40 LSPU p < 0.001, 291±54 LSPU p < 0.001, respectively) compared to the saline. It was also elevated following 1 and 10 mg/mL at the midway1 (245±48 LSPU, p < 0.05, 293±65 LSPU p < 0.001). At midway2 and apical, only the 10 mg/mL dose was effective (285±71 LSPU, p < 0.001; 302±82 LSPU, p < 0.001).

Our findings suggest a dose-dependent vasodilation to ACh, emphasizing its role in human gingival microcirculation. Only the 10 mg/mL ACh could evoke remote vasodilation 3 mm from the application. The described method could facilitate the investigation of endothelium-dependent vasodilation in disorders affecting microcirculation, such as periodontitis or diabetes.

To maintain homeostasis in the heart, endothelial cells and cardiomyocytes engage in dynamic cross-talk through paracrine signals that regulate both cardiac development and function. Here, we review the paracrine signals that endothelial cells release to regulate cardiomyocyte growth, hypertrophy and contractility, and the factors that cardiomyocytes release to influence angiogenesis and vascular tone. Dysregulated communication between these cell types can drive pathophysiology of disease, as seen in ischemia-reperfusion injury, diabetes, maladaptive hypertrophy, and chemotherapy-induced cardiotoxicity. Investingating the role of cross-talk is critical in developing an understanding of tissue homeostasis, regeneration, and disease pathogenesis, with the potential to identify novel targets for diagnostic and therapeutic purposes.