Search Results (12)

Hydrogen sulfide (H₂S), a gas traditionally considered toxic, is now recognized as a vital endogenous signaling molecule with a complex physiology. This comprehensive study encompasses a systematic literature review that explores the intricate mechanisms underlying H₂S-induced vasodilation. The vasodilatory effects of H₂S are primarily mediated by activating ATP-sensitive potassium (K_ATP) channels, leading to membrane hyperpolarization and subsequent relaxation of vascular smooth muscle cells (VSMCs). Additionally, H₂S inhibits L-type calcium channels, reducing calcium influx and diminishing VSMC contraction. Beyond ion channel modulation, H₂S profoundly impacts cyclic nucleotide signaling pathways. It stimulates soluble guanylyl cyclase (sGC), increasing the production of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels activate protein kinase G (PKG), which phosphorylates downstream targets like vasodilator-stimulated phosphoprotein (VASP) and promotes smooth muscle relaxation. The synergy between H₂S and nitric oxide (NO) signaling further amplifies vasodilation. H₂S enhances NO bioavailability by inhibiting its degradation and stimulating endothelial nitric oxide synthase (eNOS) activity, increasing cGMP levels and potent vasodilatory responses. Protein sulfhydration, a post-translational modification, plays a crucial role in cell signaling. H₂S S-sulfurates oxidized cysteine residues, while polysulfides (H₂Sn) are responsible for S-sulfurating reduced cysteine residues. Sulfhydration of key proteins like K_ATP channels and sGC enhances their activity, contributing to the overall vasodilatory effect. Furthermore, H₂S interaction with endothelium-derived hyperpolarizing factor (EDHF) pathways adds another layer to its vasodilatory mechanism. By enhancing EDHF activity, H₂S facilitates the hyperpolarization and relaxation of VSMCs through gap junctions between endothelial cells and VSMCs. Recent findings suggest that H₂S can also modulate transient receptor potential (TRP) channels, particularly TRPV4 channels, in endothelial cells. Activating these channels by H₂S promotes calcium entry, stimulating the production of vasodilatory agents like NO and prostacyclin, thereby regulating vascular tone. The comprehensive understanding of H₂S-induced vasodilation mechanisms highlights its therapeutic potential. The multifaceted approach of H₂S in modulating vascular tone presents a promising strategy for developing novel treatments for hypertension, ischemic conditions, and other vascular disorders. The interaction of H₂S with ion channels, cyclic nucleotide signaling, NO pathways, ROS (Reactive Oxygen Species) scavenging, protein sulfhydration, and EDHF underscores its complexity and therapeutic relevance. In conclusion, the intricate signaling paradigms of H₂S-induced vasodilation offer valuable insights into its physiological role and therapeutic potential, promising innovative approaches for managing various vascular diseases through the modulation of vascular tone. Full article

The beneficial cardiovascular effects of exercise are well documented, however the mechanisms by which exercise improves vascular function in diabetes are not fully understood. This study investigates whether there are (1) improvements in blood pressure and endothelium-dependent vasorelaxation (EDV) and (2) alterations in the relative contribution of endothelium-derived relaxing factors (EDRF) in modulating mesenteric arterial reactivity in male UC Davis type-2 diabetes mellitus (UCD-T2DM) rats, following an 8-week moderate-intensity exercise (MIE) intervention. EDV to acetylcholine (ACh) was measured before and after exposure to pharmacological inhibitors. Contractile responses to phenylephrine and myogenic tone were determined. The arterial expressions of endothelial nitric oxide (NO) synthase (eNOS), cyclooxygenase (COX), and calcium-activated potassium channel (K_Ca) channels were also measured. T2DM significantly impaired EDV, increased contractile responses and myogenic tone. The impairment of EDV was accompanied by elevated NO and COX importance, whereas the contribution of prostanoid- and NO-independent (endothelium-derived hyperpolarization, EDH) relaxation was not apparent compared to controls. MIE 1) enhanced EDV, while it reduced contractile responses, myogenic tone and systolic blood pressure (SBP), and 2) caused a shift away from a reliance on COX toward a greater reliance on EDH in diabetic arteries. We provide the first evidence of the beneficial effects of MIE via the altered importance of EDRF in mesenteric arterial relaxation in male UCD-T2DM rats. Full article

Background: Coronary macrovascular disease is a concept that has been well-studied within the literature and has long been the subject of debates surrounding coronary artery bypass grafting (CABG) vs. Percutaneous Coronary Intervention (PCI). ISCHEMIA trial reported no statistical difference in the primary clinical endpoint between initial invasive management and initial conservative management, while in the ORBITA trial PCI did not improve angina frequency score significantly more than placebo, albeit PCI resulted in more patient-reported freedom from angina than placebo. However, these results did not prove the superiority of the PCI against OMT, therefore do not indicate the benefit of PCI vs. the OMT. Please rephrase the sentence. We reviewed the role of different factors responsible for endothelial dysfunction from recent randomized clinical trials (RCTs) and multicentre studies. Methods: A detailed search strategy was performed using a dataset that has previously been published. Data of pooled analysis include research articles (human and animal models), CABG, and PCI randomized controlled trials (RCTs). Details of the search strategy and the methods used for data pooling have been published previously and registered with Open-Source Framework. Results: The roles of nitric oxide (NO), endothelium-derived contracting factors (EDCFs), and vasodilator prostaglandins (e.g., prostacyclin), as well as endothelium-dependent hyperpolarization (EDH) factors, are crucial for the maintenance of vasomotor tone within the coronary vasculature. These homeostatic mechanisms are affected by sheer forces and other several factors that are currently being studied, such as vaping. The role of intracoronary testing is crucial when determining the effects of therapeutic medications with further studies on the horizon. Conclusion: The true impact of coronary microvascular dysfunction (CMD) is perhaps underappreciated, which supports the role of medical therapy in determining outcomes. Ongoing trials are underway to further investigate the role of therapeutic agents in secondary prevention. Full article

Small vessel disease (SVD) is one of the most frequent pathological conditions which lead to dementia. Biochemical and neuroimaging might help correctly identify the clinical diagnosis of this relevant brain disease. The microvascular alterations which underlie SVD have common origins, similar cognitive outcomes, and common vascular risk factors. Nevertheless, the arteriolosclerosis process, which underlines SVD development, is based on different mechanisms, not all completely understood, which start from a chronic hypoperfusion state and pass through a chronic brain inflammatory condition, inducing a significant endothelium activation and a consequent tissue remodeling action. In a recent review, we focused on the pathophysiology of SVD, which is complex, involving genetic conditions and different co-morbidities (i.e., diabetes, chronic hypoxia condition, and obesity). Currently, many points still remain unclear and discordant. In this paper, we wanted to focus on new biomarkers, which can be the expression of the endothelial dysfunction, or of the oxidative damage, which could be employed as markers of disease progression or for future targets of therapies. Therefore, we described the altered response to the endothelium-derived nitric oxide-vasodilators (ENOV), prostacyclin, C-reactive proteins, and endothelium-derived hyperpolarizing factors (EDHF). At the same time, due to the concomitant endothelial activation and chronic neuroinflammatory status, we described hypoxia-endothelial-related markers, such as HIF 1 alpha, VEGFR2, and neuroglobin, and MMPs. We also described blood–brain barrier disruption biomarkers and imaging techniques, which can also describe perivascular spaces enlargement and dysfunction. More studies should be necessary, in order to implement these results and give them a clinical benefit. Full article

Nanotechnology has widespread applications in sports; however, there are very few studies reporting the use of nanotechnology to enhance physical performance. We hypothesize that a natural-mineral-based novel nanomaterial, which was developed from Japanese hot springs, might overcome the limitations. We examined if it could enhance physical performance. We conducted a treadmill exercise test on 18 students of athletic clubs at Fukushima University, Japan, and measured heart rate, oxygen consumption, maximal oxygen consumption, CO${}_2$ production, and respiratory quotient 106 times in total. The results showed that the elevation of heart rate was significantly suppressed in the natural-mineral-based nanomaterial group, while no differences were observed in oxygen consumption, maximal oxygen consumption, CO${}_2$ production, and respiratory quotient between groups. To our knowledge, this result is the first evidence where an improvement of cardiovascular and pulmonary functions was induced by bringing a natural-mineral-based nanomaterial into contact with or close to a living body without pharmacological intervention or physical intervention. This could open new avenue of biomedical industries even in an eco-friendly direction. The precise mechanisms remain a matter for further investigation; however, we may assume that endothelial NO synthase, hemoglobin and endothelium-derived hyperpolarizing factor are deeply involved in the improvement of cardiovascular and pulmonary functions. Full article

Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of aspirin on mesenteric resistance arteries and found outdiscovered the molecular mechanism underlying this action. Aspirin (10⁻¹²–10⁻⁶ M) was tested on pregnant rat mesenteric resistance arteries by a pressurized arteriography. Aspirin was investigated in the presence of several inhibitors of: (a) nitric oxide synthase (L-NAME 2 × 10⁻⁴ M); (b) cyclooxygenase (Indomethacin, 10⁻⁵ M); (c) Ca²⁺-activated K⁺ channels (Kca): small conductance (SKca, Apamin, 10⁻⁷ M), intermediate conductance (IKca, TRAM34, 10⁻⁵ M), and big conductance (BKca, paxilline, 10⁻⁵ M); and (d) endothelial-derived hyperpolarizing factor (high KCl, 80 mM). Aspirin caused a concentration-dependent vasodilation. Aspirin-vasodilation was abolished by removal of endothelium or by high KCl. Furthermore, preincubation with either apamin plus TRAM-34 or paxillin significantly attenuated aspirin vasodilation (p < 0.05). For the first time, we showed that aspirin induced endothelium-dependent vasodilation in mesenteric resistance arteries through the endothelial-derived hyperpolarizing factor (EDHF) and calcium-activated potassium channels. By activating this molecular mechanism, aspirin may lower peripheral vascular resistance and be beneficial in pregnancies complicated by hypertension. Full article

Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications. Full article

The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B₂ and/or B₁ receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs). Full article

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide–cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of Ercc1^Δ/- mice, can be used as a tool to accelerate aging. Ercc1^Δ/- mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO–cGMP signaling, can reduce the development of vasomotor dysfunction in Ercc1^Δ/- mice. Ercc1^Δ/- mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. Ercc1^Δ/- mice developed decreased reactive hyperemia, and diminished NO–cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO–cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in Ercc1^Δ/- mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease. Full article

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes. Full article

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca²⁺-activated K⁺ channels (SK_Ca and IK_Ca) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SK_Ca channels, inward rectifier K⁺ channels, Ca²⁺-activated Cl⁻ channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension. Full article

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H₂S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H₂S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H₂S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H₂S is synthesized in endothelial cells as well. Endothelial H₂S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H₂S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium-activated potassium channels. Endothelial H₂S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H₂S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H₂S-derived polysulfides directly activate protein kinase G. Finally, H₂S interacts with NO to form nitroxyl (HNO)—a potent vasorelaxant. H₂S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation. Full article