Search Results (2,159)

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

In addition to apoptosis, inflammatory cell death modalities—including pyroptosis, necroptosis, ferroptosis, NETosis, and the integrated paradigm of PANoptosis—are now established as critical drivers of diabetic kidney disease (DKD) pathogenesis. This review summarizes how key inflammatory cell death molecular mediators—such as the NLRP3 inflammasome, the RIPK1/RIPK3/MLKL axis, executioner caspases, and gasdermin-D (GSDMD)—orchestrate the death of renal cells (podocytes, tubular cells, mesangial cells, endothelium), thereby propagating inflammation and fibrosis. Preclinical studies have demonstrated the efficacy of agents targeting these pathways, highlighting their therapeutic potential. Key challenges include achieving cell type-specific targeting, overcoming redundancy among cell death pathways, and improving the translational applicability of current models. Emerging solutions include the development of precise biomarkers, kidney-targeted delivery systems, and combination therapies that concurrently target multiple cell death axes. This review synthesizes evidence establishing inflammatory cell death as a cornerstone of DKD pathology and provides a conceptual framework to guide future research and therapeutic innovation. Full article

Ischemic stroke remains one of the most catastrophic diseases in neurology, in which, due to a disturbance in the cerebral blood flow, the brain is acutely deprived of its oxygen and glucose oligomer, which in turn rapidly leads to energetic collapse and progressive cellular death. There is now increasing evidence that this type of stroke is not simply a type of ‘oxidative stress’ but rather a programmable loss-of-redox homeostasis, within which electron flow and the balance of oxidants/reductants are cumulatively displaced at the level of the single molecule and at the level of the cellular area. The advances being made in cryo-electron microscopy, lipidomics, and spatial omics are coupled with the introduction of a redox code produced by the interaction of the couples NADH/NAD⁺, NADPH/NADP⁺, GSH/GSSG, BH₄/BH₂, and NO/SNO, which determine the end results of the fates of the neurons, glia, endothelium, and pericytes. Within the mitochondria, pathophysiological events, including reverse electron transport, succinate overflow, and permeability transition, are found to be the first events after reperfusion, while signals intercommunicating via ER–mitochondria contact, peroxisomes, and nanotunnels control injury propagation. At the level of the tissue, events such as the constriction of the pericytes, the degradation of the glycocalyx, and the formation of neutrophil extracellular traps underlie microvascular failure (at least), despite the effective recanalization of the vessels. Systemic influences such as microbiome products, oxidized lipids, and free mitochondrial DNA in cells determine the redox imbalance, but this generally occurs outside the brain. We aim to synthesize how the progressive stages of ischemic injury evolve from the cessation of flow to the collapse of the cell structure. Within seconds of injury, there is reverse electron transport (RET) through mitochondrial complex I, with bursts of superoxide (O₂•⁻) and hydrogen peroxide (H₂O₂) being produced, which depletes the stores of superoxide dismutase, catalase, and glutathione peroxidase. Accumulated succinate and iron-induced lipid peroxidation trigger ferroptosis, while xanthine oxidase and NOX2/NOX4, as well as uncoupled eNOS/nNOS, lead to oxidative and nitrosative stress. These cascades compromise the function of neuronal mitochondria, the glial antioxidant capacity, and endothelial–pericyte integrity, leading to the degradation of the glycocalyx with microvascular constriction. Stroke, therefore, represents a continuum of redox disequilibrium, a coordinated biochemical failure linking the mitochondrial metabolism with membrane integrity and vascular homeostasis. Full article

Background: Thromboembolic events, though infrequent, remain a significant complication of atrial fibrillation (AF) ablation, largely related to endothelial damage. Cryoballoon (CB) and radiofrequency ablation can induce pro-coagulant responses, whereas pulsed-field ablation (PFA), a novel non-thermal electroporation-based technique, has shown tissue selectivity with potential endothelial-sparing effects. Methods: We aimed to compare PFA and second-generation CB ablation regarding endothelial injury in patients with paroxysmal AF. In this single-center prospective observational study, 25 patients with paroxysmal drug-refractory AF underwent pulmonary vein isolation using either a pentaspline PFA catheter (n = 14) or a second-generation CB catheter (n = 11). Circulating von Willebrand factor antigen (vWF) levels were assessed before and after ablation as a biomarker of endothelial damage, alongside routine laboratory and echocardiographic parameters. Procedural characteristics were also analyzed. Results: Baseline demographic, clinical, and echocardiographic data were comparable between groups. PFA was associated with significantly shorter skin-to-skin procedure time (59 vs. 94 min, p = 0.005) and left atrial dwell time (44 vs. 79 min, p < 0.001) compared with CB ablation. Importantly, vWF levels decreased significantly after PFA (−7.6%, p = 0.007), while CB ablation showed a non-significant increase (+9.5%, p = 0.155). The between-group difference in percent change of vWF was statistically significant (−5.6% vs. +8.3%, p = 0.006). Conclusions: PFA was associated with reduced endothelial injury and shorter procedural times compared with CB ablation, suggesting a potential advantage in lowering thromboembolic risk. These findings support the concept of PFA as an “endothelial sparing” ablation modality. However, the PFA procedure was associated with a significantly greater extent of myocardial injury, as reflected in circulating high-sensitivity cardiac troponin T values, compared to CB ablation (p = 0.007). Larger, randomized studies are warranted to confirm these results and evaluate long-term clinical outcomes. Full article

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

Background: Essential hypertension is associated with an increased risk of pulmonary hypertension (PH). PH is diagnosed more frequently in females. Little is known about the effects of a plant-based diet (PBD) in improving lung abnormalities in PH. Methods: We compared 28- and 40-week-old female normotensive Wistar Kyoto and spontaneously hypertensive rats (SHR), maintained from the age of 4 weeks on a control refined diet or a PBD, comprising 28% fruits, vegetables, nuts and legumes. A subset of control SHRs were switched to the PBD at 28 weeks of age. Lungs were taken for protein and histological analysis. Results: Relative to WKYs, SHRs consuming the control diet exhibited decreased lung endothelial nitric oxide synthase (eNOS). PBD consumption by SHRs prevented and reversed this phenotype. Expression of E-cadherin was also reduced in SHRs. This reduction was attenuated by PBD consumption treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2 in the lung was increased in SHRs and attenuated by PBD. The expression of activated transforming growth factor (TGF)-β1 was also attenuated by a PBD. Conclusions: The PBD favorably mediated hypertension-induced pulmonary molecular abnormalities in lung endothelium, epithelial junction and pro-fibrotic signaling. Future studies should assess the effects of a PBD in improving PH and lung function. Full article

Excessive dietary salt intake remains a critical and underestimated global health concern, strongly associated with increased cardiovascular disease risk. While the relationship between salt and arterial hypertension is well established, accumulating evidence highlights additional, blood pressure-independent mechanisms linking high salt intake with the progression of atherosclerosis. Beyond its hypertensive effects, high dietary salt directly damages the vascular endothelium by disrupting the glycocalyx, reducing nitric oxide synthesis, and increasing endothelial stiffness and inflammation. Excess sodium also impairs glycosaminoglycan buffering capacity and promotes immune cell adhesion, even in normotensive individuals. Furthermore, salt-induced dysbiosis of the gut microbiota alters the metabolic and inflammatory environment, lowering beneficial short-chain fatty acids and increasing pro-atherogenic metabolites such as trimethylamine N-oxide. Recent findings also implicate salt-driven modulation of hematopoiesis via Th17 cytokines, which enhances the production of pro-inflammatory monocytes that accelerate plaque development. These findings support the notion that high salt intake may be an independent and modifiable residual risk factor for atherosclerotic cardiovascular disease. Reducing dietary sodium—particularly from processed foods—should therefore remain a central component of both primary and secondary cardiovascular prevention. Although the optimal range of salt intake remains under discussion, a moderate reduction to below 5 g/day is considered safe and beneficial. Full article

This study aimed to elucidate the vasorelaxant mechanism of action for apigenin 7-glucoside (A7G) by integrating computational and ex vivo pharmacological approaches. Molecular docking simulations were conducted to predict the binding affinities and interactions of A7G with key vascular proteins, specifically human endothelial nitric oxide synthase (eNOS-PDB ID: 1M9M), and human intermediate (IKCa-PDB ID: 9ED1) and small-conductance (SKCa-PDB ID: 6CNN) Ca²⁺-activated K⁺ channels. The vasodilatory properties of A7G were subsequently evaluated in isolated mesenteric vascular beds (MVBs) from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). The in silico analysis indicated that A7G possesses favorable binding affinities for the 1M9M, 9ED1, and 6CNN protein targets. Pharmacological assessments demonstrated that A7G induced a dose- and endothelium-dependent reduction in perfusion pressure in MVBs from WKY and SHR rats. The vasodilatory response to A7G was completely abrogated by perfusion with a high-potassium solution or a non-selective K⁺ channel blocker. Furthermore, co-administration of apamin and TRAM-34, selective inhibitors of SKCa and IKCa, respectively, also abolished the vasorelaxant effects of A7G. Collectively, these findings suggest that the vascular effects of A7G in both WKY and SHR rats involve an endothelium-dependent mechanism, likely initiated by the activation of the NO/cGMP pathway, which culminates in the opening of IKCa and SKCa channels. Full article

Human cleft lip morphopathogenesis is a complicated process involving multiple genes and proteins. Certain factors like muscle segment homeobox 1 (MSX1) and 2 (MSX2) as well as receptor-like tyrosine kinase (RYK) are important during lip embryogenesis, while others like nuclear factor kappa-B protein 65 (NFκB p65), C-C motif chemokine ligand 4 (CCL4), and pentraxin 3 (PTX3) regulate local inflammation and immunomodulation. The exact role of these factors in human cleft morphopathogenesis remains uncertain and limits the opportunity to improve cleft treatment and possible prophylaxis. Immunohistochemistry (IHC) for MSX1, RYK, NFκB p65, and CCL4 proteins and chromogenic in situ hybridization (CISH) for MSX2, RYK, and PTX3 genes were used to analyze postnatal human cleft lip tissue (15 patients) and control tissue (6 patients). The semiquantitative counting method was used to assess factor/gene-signal-containing cells. Statistical analysis was performed. IHC findings showed decreased MSX1, NFκB p65, and CCL4 proteins in cleft lip connective tissue and endothelium, while RYK protein was decreased only in cleft connective tissue. CISH showed increases in MSX2 and RYK gene-signal-containing cells in cleft lip tissue while PTX3 did not differ from controls. Multiple statistically significant correlations were calculated. The findings are discussed in detail to determine their significance in cleft lip morphopathogenesis. Full article

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

Sialic acids are terminal monosaccharides that cap glycans on glycoconjugates. Accumulating clinical and experimental evidence shows that obesity, insulin resistance, and diabetes are accompanied by changes in sialic-acid levels. In these conditions, the sialic-acid axis is also broadly remodeled: writers (sialyltransferases), erasers (neuraminidases), and readers (Siglecs) are dysregulated across adipose tissue, liver, pancreas, endothelium, and blood, shifting insulin signaling and inflammatory tone. This review summarizes relevant studies from the perspectives of disease clinical indicators, molecular mechanisms, and interventions targeting sialic acid. Taken together, these results confirm that sialic acids and related molecules play important roles in multiple metabolic diseases; however, controversies remain due to differences in glycan structure, isoforms, and tissue specificity, particularly regarding the precise roles of neuraminidases. Future studies should build on advanced, standardized glycomic and glycoproteomic measures to define molecule- and tissue-specific roles of sialic acids in metabolic disease, enabling reliable biomarkers and guiding targeted therapy. Full article

Atherosclerosis is characterized by atherosclerotic plaque formation in large and medium vessels, mediated by endothelial cell (EC) dysfunction, altered contractility of Vascular Smooth Muscle Cells (VSMCs) and recruitment of blood leukocytes to the injured vascular endothelium. These include macrophages (MØ), T lymphocytes, and dendritic cells, which drive the production of many inflammatory mediators and the process of chronic inflammation. Also, de-differentiation or phenotypic switching of VSMCs contributes to vascular remodeling and the pathogenesis of atherosclerosis. Likewise, MØ plasticity and the presence of different phenotypes have a major effect on atherosclerotic plaque formation. The multi-functional transcriptional regulator and pluripotency factor Krüppel-like factor 4 (KLF4) acts as a gatekeeper of VSMC phenotypic switching and MØ polarization during vascular inflammation and atherosclerosis. Similarly, pro-inflammatory pathways activated by Toll-like receptor (TLR)4 and Interferon gamma (IFNγ) emerge as key components of VSMC and MØ plasticity, tightly regulated by Signal Transducer and Activator of Transcription (STAT)s, Interferon Regulatory Factor (IRF)s, and Nuclear factor-κB (NF-κB). Recent discoveries predict a collaborative role of these transcription factors in different transcriptional mechanisms connected to inflammation and atherosclerosis. This review provides novel insight into the transcriptional regulatory interplay between KLF4, STATs, IRFs, and NF-κB in VSMC phenotypic switching and MØ polarization during atherogenesis. Detailed understanding of these transcriptional networks will enable us to develop novel diagnostic and therapeutic strategies to combat vascular proliferative diseases, including atherosclerosis. Full article

Human hemangioblastoma is a benign, slow-growing, highly vascular neoplasm. The tumor most commonly arises in the cerebral hemispheres and cerebellum, where it is more frequently observed in patients with von Hippel–Lindau disease. In veterinary medicine, hemangioblastoma has only been described in the central nervous system of dogs and in the skin of lambs. Our study aimed to characterize the clinical and neuropathological features of five cases of canine spinal cord hemangioblastoma and one case of sciatic nerve localization, and to compare these results with those reported in the veterinary literature. Diagnoses were achieved by neurological examination, neuroimaging, surgery or post-mortem examination, histopathology, and immunohistochemistry. All tumors were composed of numerous, haphazardly arranged capillaries lined by plump endothelium and interstitial fusiform to stellate stromal cells. Immunohistochemically, the stromal cells were strongly immunolabeled with NSE and carbonic anhydrase IX and were negative for von Willebrand factor VIII and inhibin-α. Canine hemangioblastoma exhibits morphological and immunohistochemical features comparable to the human counterpart, although the latter is mostly positive for inhibin-α. Surgery may be effective in cases of intradural-extramedullary and peripheral nerve locations, as in humans. This is the first report of peripheral nerve hemangioblastoma in animals. Full article

6-Nitrodopamine is an endogenous catecholamine responsible for numerous biological activities. Here, an improved method for the synthesis of both 6-nitrohomovanillic acid (6-NHVA) and its regioisomer 5-nitrohomovanillic acid (5-NHVA) is reported. The developed one-step synthetic procedures ensured the efficient preparation of the target compounds in good yields. Comprehensive structural characterization was achieved through one- and two-dimensional NMR studies and by high-resolution mass spectrometry (HR-MS/MS). The presence of both substances was identified in human amniotic fluid by LC-MS/MS. Full article

Nitric oxide is a gaseous molecule endogenously produced by endothelial cells, which stands out for its vascular tone regulation effects after crossing through the endothelium and diffusing to smooth blood vessel muscle cells. Reduced nitric oxide bioavailability contributes to the development of hypertension, atherosclerosis, worsening endothelial function, arterial stiffness, and ineffective stimulation of smooth muscle relaxation. L-citrulline, an amino acid found in high concentrations in watermelon, may serve as a recycling substrate, increasing L-arginine availability and, consequently, nitric oxide synthesis. By enhancing circulating L-arginine, L-citrulline indirectly improves the synthesis and bioavailability of nitric oxide, promoting smooth muscle vasodilation. Herein, this narrative review critically examines current evidence of the cardiovascular benefits of L-citrulline ingestion obtained exclusively through watermelon consumption, exploring the nutritional and bioactive composition of the edible parts of this fruit and the metabolism and effects of L-citrulline supplementation on vascular and metabolic physiology and proposing directions for future research, such as long-term studies and studies in specific populations. The beneficial effects of oral L-citrulline ingestion through watermelon require additional evidence, but it has already been demonstrated that it does not undergo hepatic metabolism, instead being transported to the kidneys to participate in de novo L-arginine synthesis. The generation of endogenous NO then causes positive biochemical, hemodynamic, and vascular effects, remodeling the physio-pathological conditions of those adults that present risk factors for cardiovascular diseases. Full article