Search Results (2,017)

Coronary artery vasospasm (CAV) is a transient, reversible constriction of the epicardial coronary arteries that reduces coronary blood flow and may cause myocardial ischemia. Despite its clinical significance, CAV remains underdiagnosed and can present as chest pain, acute coronary syndrome, malignant arrhythmias or sudden cardiac death. Vasospasm may occur in both angiographically normal coronary arteries and at sites of pre-existing atherosclerotic stenosis. The pathophysiology of CAV is multifactorial and involves vascular smooth muscle cells (VSMCs) hyperreactivity, endothelial dysfunction, chronic inflammation and autonomic dysregulation. VSMCs contraction is mediated by phosphorylation of the myosin light chain (MLC) through calcium (Ca²⁺)/calmodulin-dependent myosin light chain kinase (MLCK), while relaxation is regulated by myosin light chain phosphatase (MLCP). Increased intracellular Ca²⁺ levels and enhanced Ca²⁺ sensitivity contribute to excessive vasoconstriction. Rho-kinase (ROCK) plays a pivotal role in sustained vasospasm by inhibiting MLCP, thereby promoting prolonged smooth muscle contraction. Endothelial dysfunction contributes to CAV by disrupting normal vascular tone regulation, largely as a result of decreased nitric oxide (NO) mediated vasodilation. Chronic low-grade inflammation and oxidative stress exacerbate both endothelial dysfunction and VSMCs contraction. Understanding these molecular mechanisms is essential for identifying novel therapeutic targets. Emerging treatment strategies, including ROCK inhibitors, endothelin receptor antagonists and anti-inflammatory agents, may improve outcomes in patients with refractory CAV. Full article

Endothelial dysfunction (ED) is an early event in cardiovascular and metabolic diseases, including atherosclerosis, diabetes, and hypertension. Emerging evidence highlights the interplay between chronic inflammation and oxidative stress, collectively termed OxInflammation, as a major driver of vascular injury and impaired tissue repair. Among the key mediators of this response is the Nod like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multiprotein complex that promotes the release of inflammatory cytokines, including Interleukin 1β (IL-1β) and Interleukin-18 (IL-18), and induces gasdermin D-mediated pyroptotic cell death. Activation of NLRP3 disrupts endothelial function, reduces nitric oxide availability, and accelerates vascular inflammation and injury. This review discusses current evidence on pharmacological strategies targeting NLRP3 inflammasome signaling using both natural and synthetic inhibitors. Studies have shown that inhibiting NLRP3 can reduce inflammation and oxidative stress, preserve endothelial integrity, improve vascular function, and support tissue repair. Several NLRP3-targeting compounds have advanced into early-phase clinical trials, showing encouraging safety profiles and efficacy in individuals with cardiovascular risk factors. By integrating the emerging concept of OxInflammation with endothelial dysfunction, this review critically evaluates the therapeutic and translational potential of NLRP3 inflammasome inhibition in cardiovascular and metabolic disorders. Collectively, the available evidence supports NLRP3 as a promising therapeutic target for restoring endothelial homeostasis and promoting vascular repair. However, further clinical studies are needed to establish long-term efficacy, optimal dosing strategies, and appropriate patient selection criteria. Full article

Diabetic kidney disease (DKD) represents the single most common etiology of chronic kidney disease and end stage kidney disease globally, a burden that continues to expand in direct proportion to the worldwide growth of the diabetes epidemic. The pathogenesis of DKD is multifactorial, involving metabolic, hemodynamic, inflammatory, and fibrotic pathways. Among these, aldosterone has emerged as a key mediator of kidney injury, extending beyond its traditional role in sodium balance and blood pressure regulation. Through activation of both MR-dependent transcriptional processes and MR-independent signaling cascades, aldosterone drives a coordinated pattern of renal injury encompassing oxidative stress generation, endothelial dysfunction, podocyte damage, inflammatory cell recruitment, and progressive interstitial fibrosis. Current therapies targeting the renin–angiotensin–aldosterone system (RAAS), including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, have significantly improved outcomes in DKD. Despite these advances, a considerable degree of residual cardiovascular and renal risk persists, attributable in part to the incomplete attenuation of aldosterone activity and the well-characterized phenomenon of aldosterone escape under sustained RAAS blockade. Aldosterone synthase inhibitors (ASIs) represent a mechanistically distinct therapeutic approach that targets aldosterone overproduction at its enzymatic source, potentially addressing both MR-dependent and independent pathways. Early clinical trials evaluating the efficacy of ASIs have demonstrated promising effects on blood pressure and albuminuria. This review summarizes the role of aldosterone in DKD pathogenesis, evaluates current therapeutic approaches, and discusses emerging evidence supporting ASIs as a potential addition to the evolving treatment landscape. Full article

Diabetes mellitus represents a major global health challenge with rapidly increasing prevalence and substantial morbidity driven by metabolic and vascular complications. Extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication and are increasingly implicated in the pathogenesis and progression of diabetes. This review summarizes current knowledge on EV biology, including their classification, cellular sources, biogenesis, uptake mechanisms, and molecular cargo. We discuss the contribution of EV-associated microRNAs to immune dysregulation and β-cell damage in type 1 diabetes mellitus (T1DM), as well as the role of EVs in insulin resistance, metabolic signaling, and vascular dysfunction in type 2 diabetes mellitus (T2DM). Particular emphasis is placed on EV-mediated modulation of endothelial function, angiogenesis, and tissue repair, alongside their involvement in the impairment of insulin receptor integrity. We further explore how lifestyle factors may influence EV composition and function, highlighting their potential integration into preventive strategies. Finally, we evaluate the emerging therapeutic potential of EVs as biomarkers and delivery systems, while addressing current limitations and future directions. Collectively, EVs represent a promising frontier in understanding diabetes pathophysiology and developing innovative diagnostic and therapeutic approaches. Unlike previous reviews that examine EVs separately as biomarkers or therapeutic vehicles, this review integrates emerging evidence supporting EVs as mediators of systemic communication linking pancreatic islets, adipose tissue, immune cells, vascular endothelium, kidney, heart, and retina throughout diabetes progression. We further critically evaluate translational barriers that currently limit clinical implementation of EV-based diagnostics and therapeutics. Full article

Atherosclerosis (AS) is the primary underlying cause of cardiovascular and cerebrovascular diseases. The occurrence and development of AS are closely related to lipid deposition, chronic inflammation, phenotypic modulation of vascular smooth muscle cells (VSMCs), and extracellular matrix (ECM) remodeling. Numerous studies indicate that low-density lipoprotein receptor-associated protein 1 (LRP1), as a multifunctional receptor, contributes to vascular homeostasis in AS and vascular remodeling by regulating lipid handling, inflammatory responses, transforming growth factor beta (TGFβ) signaling, and platelet-derived growth factor receptor beta (PDGFRβ) trafficking. Rather than treating the LRP1-TGFβ-PDGFRβ relationship as a fully established linear pathway, this review distinguishes demonstrated mechanisms from inferred cross-talk and proposes an integrated, cell- and stage-dependent regulatory model. This article systematically elaborates on the structure and function of LRP1; LRP1-mediated regulation of TGFβ and PDGFRβ in AS and vascular remodeling; the possible relationship among LRP1, TGFβ, and PDGFRβ; and cell-specific effects in VSMCs, macrophages, endothelial cells, and pericytes. Meanwhile, this article summarizes potential translational strategies such as lipid-lowering, anti-inflammatory therapy, PDGFRβ inhibitor repositioning, TGFβ pathway modulation, biomarker-based stratification, and LRP1-targeted delivery. A deeper understanding of the cell-specificity and stage-dependence of the LRP1-TGFβ-PDGFRβ signaling network may help elucidate the progression mechanism of AS and provide new ideas for risk stratification and precise intervention. Full article

Hepatocellular carcinoma (HCC) is sustained by coordinated interactions among malignant hepatocytes, immune cells, and stromal populations that collectively drive tumor growth, immune evasion, and vascular remodeling. Using integrative single-cell transcriptomics on 93,032 cells from tumor and healthy human liver, we characterized cell-type-specific transcriptional programs underlying immunometabolic reprogramming and reconstructed the intercellular communication circuits that maintain the tumor microenvironment. Malignant hepatocytes displayed upregulation of genes encoding both glycolytic and oxidative phosphorylation (OXPHOS) metabolic enzymes, consistent with metabolic plasticity, while concurrently suppressing genes involved in antigen presentation—a transcriptional pattern indicative of coordinated metabolic and immune-evasive reprogramming. Tumor-associated macrophages acquired TREM2-enriched, lipid-handling phenotypes consistent with immunosuppressive polarization, and tumor endothelial cells upregulated angiocrine and extracellular matrix programs while silencing innate immune outputs. Ligand–receptor inference revealed a qualitative rewiring of intercellular communication: the antigen-presentation-centered network of the healthy liver was replaced by a tumor-driven architecture dominated by pro-angiogenic, ECM–integrin, inflammatory chemokine, and lipid-associated signaling circuits, with malignant hepatocytes, TAMs, and TECs collectively assuming the dominant signaling burden. These findings establish that HCC progression is an emergent property of a stabilized multicellular network, rather than the autonomous behavior of malignant cells, and define cooperative immunometabolic modules that constitute tractable targets for combinatorial therapeutic intervention. Full article

Background: Synaptic plasticity in neurodegenerative disorders (NDs), cognitive impairment, and mental health conditions is regulated by brain-derived neurotrophic factor (BDNF). Even healthy individuals have different levels, which are affected by complex epigenetic, inflammatory, and metabolic regulation. BDNF expression changes are associated with both typical and abnormal aging, as well as mental health conditions. These changes affect brain areas that are crucial for memory, such as the hippocampus and the parahippocampal cortex. Neurotrophins (NTs), including nerve growth factor (NGF) and BDNF, are essential for neuronal differentiation via tropomyosin receptor kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). Dysregulated NTs signaling contributes to synaptic dysfunction and neuroinflammation. Objective: This systematic review synthesizes preclinical evidence of the potential of naturally derived compounds to modulate NTs for neuroprotection and their incorporation into novel foods. Methodology: A review of major databases found studies that examined the impact of dietary polyphenols and other bioactive substances on NT signaling oxidative stress, inflammation, and neuronal plasticity. Results: Compounds such as epigallocatechin gallate, resveratrol, curcumin, quercetin, and flavanols, can positively impact NTs, reducing reactive oxygen species/reactive nitrogen species, enhancing cell survival, and increasing the expression of trophic factors such as nuclear factor erythroid 2-related factor 2 (Nrf2), NGF, and vascular endothelial growth factor in neural stem cells. However, their bioavailability, optimal dosage, and dietary interactions require further research. Conclusions: The consumption of BDNF-promoting foods can potentially stimulate BDNF synthesis, support optimal neurotransmission, and fortify neural plasticity. Evidence supports a polyphenol-rich diet for preventing NDs and promoting brain health. Observational studies consistently support the protective effects of polyphenols on brain health through their impact on the gut–brain axis. Full article

There are a few molecules that are regularly used as markers for lymphatic endothelial cells (LECs) such as the adhesion molecule CD31/PEACAM1, the transcription factor PROX1, the Vascular Endothelial Growth Factor Receptor-3 (VEGFR3/FLT4), the glycoprotein podoplanin, and the hyaluronan receptor LYVE1. However, none of the molecules are exclusively expressed in LECs, and there is molecular and functional heterogeneity of LECs in initial lymphatics, lymphatic collectors and lymph nodes. Therefore, a combination of markers must be applied to identify lymphatics. This is particularly true for the characterization of conditions such as lymphatic malformations or cancers, in which the molecular profile of vessels may be variable or abnormal. Here we present two molecules that can help distinguish between endothelial cells of blood and lymphatic vessels: the scaffold protein liprin β-1 (PPFIBP1) and the intermediate filament synemin. We collected own data on the RNA and protein expression of the two molecules in humans, and studied publicly available databases. PPFIBP1 appears to be a suitable marker of LECs in initial lymphatics, collectors and lymph nodes, while synemin appears to be more restricted to initial lymphatics. We hope this will stimulate monoclonal antibody development and help expand the range of LEC markers in health and disease. Full article

CXCL8, a pro-inflammatory chemokine, which can be induced by TNF-α or IL-1, is responsible for the recruitment and activation of neutrophils. Chemokines interact with glycosaminoglycans on endothelial cells and are thus protected from degradation and sequestration, holding them in an optimal position for recruiting immune cells. Inhibiting the interaction of chemokines with their glycosaminoglycan co-receptors represents an attractive approach for the treatment of chemokine-mediated diseases. Two polyketide-pyrone compounds, PA501 and PA502 were synthesized, which bind to CXCL8 with affinities higher than the natural glycosaminoglycan ligand heparan sulfate, and in a similar range as heparin. Significant structural changes were induced in the chemokine by interacting with the two compounds, as expressed in fluorescence and far-UV CD experiments. In filter binding assays, both compounds were found to displace heparan sulfate efficiently from CXCL8, with PA501 displaying the highest competition efficacy. Using a C-terminally truncated form of the chemokine, CXCL81-58, which lacks the main glycosaminoglycan-binding α-helical domain, the two compounds are suggested to use—to a varying degree—different binding sites on the protein, which have also been proposed for the natural heparan sulfate ligand. In a transmigration assay, PA501 and PA502 exhibited dose-dependent modulation of CXCL8-induced neutrophil mobilization and migration. The compounds PA501 and PA502 may thus be regarded as early novel lead compounds in the quest for anti-inflammatory, chemokine-targeting drugs. Full article

Research on diabetic retinopathy (DR) usually emphasizes hyperglycemia and other causes like dyslipidemia, which are still not well understood. This study examined the effects of palmitic acid (PA) exposure, alone and combined with high glucose (G25), on Müller Glial Cell (MGC) dysfunction and angiogenic signaling. Primary MGC cultures were treated with G25 (25 mM), PA (250 µM), or PA + G25 for 24 and 48 h, followed by assessments of cell viability and analysis of the Vascular Endothelial Growth Factor (VEGFA)/VEGFA receptor 2 (VEGFR2) pathway through immunofluorescence, Western blot, and ELISA. Additionally, Gaussian mixture models (GMMs) were used to identify phenotypic subpopulations based on fluorescence intensity. The results showed that while hyperglycemia did not cause significant changes, PA and PA + G25 induced apoptosis-related cell death and significantly increased the expression of VEGFA, VEGFR2, HIF-α, and SP1. Although broad phenotypic diversity was observed at 24 h, by 48 h, a distinct shift towards an angiogenic phenotype was noted, with significantly elevated VEGFA/VEGFR2 levels. In summary, this research demonstrates that PA acts as a critical inducer of an angiogenic secretory phenotype in MGCs, indicating that lipid-mediated signaling plays a vital role in neovascularization in DR, possibly independent of glucose levels. Full article

Ischemic diseases are characterized by the functional collapse of endothelial cells (ECs) triggered by insufficient tissue perfusion. Given that mitochondria serve as the metabolic hub of ECs, their homeostatic imbalance, which is manifested by adenosine triphosphate (ATP) depletion, reactive oxygen species (ROS) bursts, and mitochondrial permeability transition pore opening, serves as the initiating factor driving impaired angiogenesis and tissue necrosis. In this study, we engineered an integrated nanosystem (Tan-CDs@AS-IV) by transforming Tanshinone into antioxidant carbon dots to encapsulate Astragaloside IV, achieving multi-level synergistic regulation of mitochondrial function. Our results demonstrate that Tan-CDs@AS-IV possesses superior structural stability and cellular internalization capabilities, significantly enhancing the migration and tubulogenesis of ECs under ischemic stress. Mechanistically, Tan-CDs@AS-IV effectively scavenges mitochondrial ROS and restores membrane potential and ATP production. Crucially, the nanosystem orchestrates mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) upregulation while simultaneously facilitating intercellular mitochondrial transfer through Connexin 43 (Cx43)-mediated gap junctions. This synergistic “endogenous amplification and intercellular replenishment” model establishes a robust mitochondrial quality control relay. By reconstructing cellular energy homeostasis, this study provides a novel nanoengineering strategy for the targeted therapy of ischemic diseases. Full article

Background/Objectives: Growth differentiation factor-15 (GDF-15) is a protein that belongs to the transforming growth factor beta superfamily and has been found elevated in cases of organ injury such as liver, kidney, heart, and lung, as well as cardiovascular diseases and cancer. Soluble urokinase plasminogen activator receptor (suPAR) is a protein which is expressed mainly on immune cells and endothelial and smooth muscle cells, and is a marker of severity and intensity of inflammation in acute and chronic diseases. The aim of the present study was to compare GDF-15 serum levels between patients with acute cerebrovascular incidents and healthy controls and to investigate the possible correlation of GDF-15 serum levels and inflammatory markers, such as serum C-reactive protein (CRP) and plasma suPAR, in the above-mentioned groups. Methods: This is a retrospective study. Thirty-one patients were included in the study, with a mean age ± SD of 67 ± 13 years, compared to 18 age-matched healthy controls. Results: In the patient group a statistically significant positive correlation of serum levels of GDF15 values with suPAR and CRP emerged (rs = 0.516, p = 0.003) and (rs = 0.409, p = 0.022), respectively, and no significant correlation was found in the group of controls (rs = 0.271, p = 0.277) and (rs = 0.423, p = 0.080), respectively. Conclusions: These findings support the role of inflammation as a key underlying mechanism in acute cerebrovascular injury and suggest that GDF-15 may serve as a valuable adjunct biomarker for assessing disease severity and inflammatory burden. Full article

Vascular endothelial cells (ECs) coordinate with osteogenic processes to establish the specialized vasculature of bone tissue, where endothelial cells and bone cells interact, and bone cells regulate EC proliferation and differentiation. However, it remains unclear how ECs and bone cells are coordinated during early bone formation and whether these interactions differ between endochondral ossification (e.g., femur) and intramembranous ossification (e.g., skull). To address this question, we analyzed endothelial and osteogenic marker expression in the femur and skull between postnatal days 3 and 39. We identified distinct expression patterns of endothelial markers (Endomucin, VE-cadherin and CD31) and osteogenic markers (Osterix, Cbfa1 and BGLP) during osteogenesis in these tissues. In the femurs, endothelial marker expression alternated with the expression of osteogenic markers, suggesting potential reciprocal regulation. In contrast, in the skull, endothelial and osteogenic markers exhibited similar temporal expression patterns without alternation. We also analyzed the expression of VEGF and its receptor FLK1. In the femur, VEGF expression paralleled osteogenic marker expression, whereas in the skull VEGF expression differed from both osteogenic and endothelial marker patterns. Together, these results demonstrate that the coordination of endothelial and osteogenic marker expression, as well as VEGF signaling, differs between endochondral and intramembranous ossification, suggesting distinct modes of interaction between endothelial and bone cells during the formation of long and flat bones. Full article

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease of the pulmonary vasculature characterized by obliterative remodeling of small pulmonary arteries, leading to sustained elevation of pulmonary vascular resistance, right ventricular failure, and premature death. The diagnostic gold standard remains right heart catheterization, requiring a mean pulmonary artery pressure greater than 20 mmHg at rest, a pulmonary arterial wedge pressure of 15 mmHg or below, and a pulmonary vascular resistance exceeding 2 Wood units. PAH is an autosomal dominant disorder with markedly incomplete penetrance of approximately 20–30%, indicating that germline mutations alone are insufficient to cause disease. Disease manifestation requires additional “second hits”, including chronic hypoxia, systemic inflammation, hemodynamic stress, hormonal influences, and common genetic modifiers such as single-nucleotide polymorphisms (SNPs). This genetic and environmental complexity underpins the broad clinical heterogeneity observed across PAH subtypes, which include idiopathic PAH, heritable PAH, and disease associated with connective tissue disorders, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, and drug or toxin exposure. This review provides a comprehensive and critical appraisal of the molecular-genetic architecture of PAH. Thirty genes have now been implicated in disease pathogenesis, spanning seven functional categories: receptors of the TGF-β/BMP signaling family (BMPR2, ACVRL1, ENG, BMPR1B); circulating BMP ligands (GDF2, BMP10); transcription factors (TBX4, SOX17, KLF4, FOXF1, SMAD1, SMAD4, SMAD9); membrane and polyamine transporters (ATP13A3, AQP1); potassium channel regulators (KCNA5, KCNK3, ABCC8); metabolic and mitochondrial genes (EIF2AK4, NFU1, GGCX); signaling receptors and structural proteins (NOTCH3, KDR, CAV1, PLEKHH2); vasoactive and extracellular matrix regulators (KLK1, CBLN2, CD248); and epigenetic regulators (TET2, TOPBP1). Among these, BMPR2 is the dominant contributor, accounting for 53–86% of heritable PAH and 14–35% of idiopathic cases. The remaining genes each account for fewer than 5% of cases individually, collectively reflecting a broad landscape of rare and ultra-rare genetic contributions. For each gene, we critically evaluate the strength of genetic evidence, pathogenic mechanisms, degree of mechanistic resolution, and clinical relevance. We further discuss the contribution of emerging technologies, including whole-genome sequencing, single-cell and spatial transcriptomics, multi-omics integration, iPSC-derived vascular models, and artificial intelligence, to expanding the PAH genetic architecture beyond single-gene discovery. A key theme across this landscape is convergence: despite mechanistic diversity at the gene level, most PAH-associated variants ultimately impair endothelial quiescence, promote smooth muscle proliferation, and drive apoptosis resistance through disruption of BMP signaling amplitude, transcriptional stability, ion channel homeostasis, metabolic integrity, or epigenetic regulation. This convergence supports both a unified therapeutic rationale and a precision medicine framework for genotype-stratified intervention in PAH. Full article

Background: Brain microvascular endothelial cells (BMECs) form the blood–brain barrier (BBB), a highly selective interface that restricts paracellular diffusion and regulates the transport of nutrients and drugs into the central nervous system via specialized transporters and receptors. Tight junction-associated protein 1 (Tjap1), also termed protein incorporated later into tight junctions (Pilt), has been localized to tight junctions (TJs) in epithelial cells and to the trans-Golgi network in fibroblasts; however, its expression, subcellular localization, and functional significance in BMECs are still unknown. Methods: We characterized Tjap1 subcellular localization in mouse and human BMEC cell lines as well as primary mouse BMECs by immunofluorescence with and without pharmacological Golgi disruption by treatment with Brefeldin A, Golgicide A or Pitstop 2. CRISPR/Cas9-mediated Tjap1 knockout cells were generated and examined with regard to their Golgi morphology using immunostaining. Tjap1 mRNA localization was examined by RNAscope in situ hybridization. Quantitative real-time PCR and Western blot was performed to assess the expression of BBB-associated efflux transporters, solute carrier transporters, and cellular receptors in control and Tjap1 knockout cells. Results: Tjap1 predominantly localized to the cis-Golgi compartment, co-localizing with Gm130 rather than Tgn38, and was absent from TJs in BMECs. Tjap1 knockout induced pronounced Golgi fragmentation BMECs. Importantly, Tjap1 knockout significantly downregulated mRNA-expression of Abcb1a, Abcb1b, Abcc4, Slc2a1, Slc7a1, Slc7a5 and Tfrc, while Abcg2 was upregulated. At the protein level, a decrease in the protein levels of Abcb1, Abcc4, Slc2a1, Slc7a1, and Tfrc was observed in Tjap1 knockout cEND cells. Conclusions: In BMECs, Tjap1 is a cis-Golgi-associated protein required for the structural integrity of the Golgi apparatus. Its deletion is associated with Golgi fragmentation and significant alterations in the mRNA and protein expression of drug transporters and receptors at the BBB. These findings identify Tjap1 as a candidate regulator of both Golgi architecture and the BBB transporter profile in vitro, with potential implications for modulating drug transport across the BBB. Full article