Search Results (4,627)

Endothelial cells (ECs) play a critical role in physiological processes, including regulating blood fluidity, angiogenesis, and regulating the immune response. Integrins, which participate in sensing external stimuli and signal transduction, are crucial for the proper functioning of ECs. Like other cells, ECs undergo senescence, which is associated with their dysfunction and contributes to increased susceptibility to cardiovascular disease. However, the role of integrin-dependent pathways in endothelial senescence is poorly understood. Here, we identify integrin-linked kinase (ILK) as a crucial factor modulating endothelial function and senescence. Using two complementary models, replicative and stress-induced premature senescence, in endothelial cells of different origins, we show that the senescent endothelium shows phenotypic and functional dysfunction. Furthermore, we revealed that these modulations correlated with ILK downregulation. Functionally, ILK depletion in young ECs was sufficient to trigger a senescence-associated phenotype and manifested key features of endothelial dysfunction. In line with this, ILK restoration in senescent cells reduced selected senescence markers and improved endothelial function. Together, these findings show that ILK is not only correlated with endothelial ageing but also works as an active regulator of senescence-linked endothelial dysfunction. Thus, ILK, as a link between adhesion-dependent signalling and endothelial ageing, is a potential target for limiting age-associated vascular decline. Full article

Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. While elevated intraocular pressure (IOP) remains the primary modifiable risk factor, a certain proportion of patients continue to deteriorate despite adequate IOP control, pointing to IOP-independent mechanisms of neurodegeneration. Oxidative stress—defined as an imbalance between the production of reactive oxygen species and the capacity of endogenous antioxidant defenses—has emerged as a central, multi-tiered contributor to glaucoma pathogenesis. In the anterior segment, chronic oxidative damage to the trabecular meshwork impairs aqueous humor outflow and drives IOP elevation. In addition, oxidative stress may impair ocular biomechanical integrity, including corneal hysteresis and lamina cribrosa, resulting in heightened susceptibility to IOP fluctuations. In the posterior segment, oxidative stress directly contributes to mitochondrial damage and vascular endothelial injury, leading to RGC apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway coordinates the principal endogenous antioxidant response, while nicotinamide adenine dinucleotide (NAD⁺) depletion links redox imbalance to metabolic vulnerability of RGCs. This narrative review synthesizes evidence published up to March 2026 on the molecular mechanisms of oxidative stress in glaucoma, the role of biomarkers in aqueous humor and systemic circulation, and the translational landscape of antioxidant-based neuroprotection—including nicotinamide, coenzyme Q10, alpha-lipoic acid, and Nrf2-activating compounds. We highlight gaps between preclinical promise and clinical evidence, and outline priorities for future randomized controlled trials. Full article

Dengue is the most prevalent arthropod-borne viral disease, caused by infection with the dengue virus (DENV). Severe dengue is characterized by significant vasculopathy involving a proinflammatory and procoagulant state associated with increased vascular permeability. However, the host–virus interactions driving this process remain incompletely elucidated. Monocytes (Mø) are primary target cells during DENV infection and actively release extracellular vesicles, like microparticles (MPs), mediating intercellular communication, contributing to dengue pathogenesis. Here, we evaluated whether MPs released by DENV-infected monocytes represent a previously underappreciated mechanism contributing to dengue-associated vascular dysfunction. The vascular endothelium plays a determining role in the response to injury because it functions as a regulatory interface during hemostasis (coagulation–fibrinolysis–inflammation) and by preserving the endothelial barrier. We found that these vesicles transport viral proteins (E and NS1), exhibit a procoagulant profile that promotes thrombin generation, and enhance endothelial vascular cell (EVC) activation. DENV-infected THP-1 Mø MPs interaction induces a shift toward a procoagulant, proinflammatory, and proadherent phenotype, characterized by increased expression of PAR-1, TF, ICAM-1, and VCAM-1, reflecting the establishment of a sustained HMEC-1 EVC activation that compromises vascular barrier integrity. This leads to increased permeability, a hallmark of DENV-associated vasculopathy and a central event in the progression to severe dengue. Full article

Chronic lung disease of prematurity (CLD) is a common complication of preterm birth with a complex pathology. Recent epidemiologic studies have identified a link between neonatal exposure to di(2-ethylhexyl) phthalate (DEHP), frequently used in medical equipment, and the development of CLD. We hypothesize that DEHP exposure in the early neonatal period contributes to lung injury in newborn rats. Newborn rat pups were raised in one of the following environments: room air (RA), RA + DEHP, hyperoxia (60% oxygen), and hyperoxia + DEHP. Ambient DEHP was inhaled at a dose of 25 mg/m³ for 6 h daily for 14 days. Lung tissue and blood samples were collected on the 14th day of life. Independent exposure to DEHP and hyperoxia resulted in thicker pulmonary septal walls, fewer alveoli, increased pulmonary polymorphonuclear leukocytes and myeloperoxidase (MPO) activity and decreased expression of CD31 on endothelial cells in lung tissue. Additionally, DEHP-exposed rats showed higher serum malondialdehyde (MDA) levels and reduced vascular endothelial growth factor (VEGF) mRNA and protein levels compared to controls. Our experiments demonstrate that inhaled DEHP, with or without hyperoxia, resulted in a similar pattern of morphological lung injury and inflammation characteristic of CLD, suggesting an association with CLD of prematurity. Full article

Lipedema is a chronic adipose tissue disorder characterized by disproportionate and often painful enlargement of the extremities, occurring predominantly in women. Despite increasing clinical recognition, the underlying pathophysiology remains incompletely understood and is likely multifactorial. Existing evidence suggests contributions from vascular alterations, adipose tissue remodeling, inflammatory activation, hormonal influences, and lymphatic dysfunction. This review proposes a hypothesis-generating integrative framework in which lipedema may reflect a regenerative imbalance of subcutaneous adipose tissue. Within this model, genetically and hormonally modulated endothelial permeability could promote activation of perivascular adipose-derived stromal/stem-cell niches and stromal vascular fraction signaling pathways, thereby facilitating coupled angiogenesis and adipogenesis. Progressive adipocyte hyperplasia and hypertrophy may subsequently contribute to inflammatory remodeling, pain generation, and secondary impairment of dermal and subdermal lymphatic drainage. The proposed framework attempts to integrate clinical, histological, imaging, molecular, and endocrine observations into a biologically coherent conceptual model. At the same time, the review emphasizes the current limitations of the available evidence, the heterogeneity of lipedema phenotypes, and the ongoing controversies regarding disease progression, obesity overlap, and the relative role of lymphatic dysfunction. Finally, the potential mechanistic rationale of lymphatic-sparing liposuction is discussed in the context of tissue decompression, restoration of lymphatic transport, and interruption of persistent adipose remodeling. The model presented here should be interpreted as a hypothesis-generating conceptual scaffold requiring prospective validation. Importantly, the present framework should be interpreted as a biologically plausible and hypothesis-generating conceptual model rather than a definitive mechanistic doctrine. Several proposed interactions remain associative and require prospective biological validation. Full article

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with cardiovascular diseases; however, the mechanisms underlying PFAS-induced vascular endothelial injury remain incompletely understood. In this study, we systematically evaluated the effects of 15 PFAS on endothelial morphology and cell viability with different carbon-chain lengths and functional groups in cultured bovine aortic endothelial cells. Morphological observations and MTT assays revealed that perfluorononanoic acid, perfluorodecanoic acid (PFDA), and perfluorooctane sulfonate (PFOS) markedly reduced cell viability, with estimated concentrations producing a 50% reduction in viability of 60.9, 34.7, and 87.3 µM, respectively, whereas the other tested PFAS did not reduce viability by 50% at concentrations up to 100 µM in bovine aortic endothelial cells. Among the perfluoroalkyl carboxylic acids, the reduction in cell viability increased with increasing carbon-chain length. Among perfluoroalkyl sulfonates, PFOS caused the greatest reduction in cell viability, whereas perfluorodecanesulfonate did not induce clear endothelial damage. Comparative analyses across multiple cell types showed that PFDA reduced cell viability broadly across all cell types examined, whereas PFOS caused a greater reduction in cell viability in bovine-derived cell types examined than in human- or porcine-derived cell types examined. Since PFDA and PFOS were the most cytotoxic compounds among perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonates, respectively, in bovine aortic endothelial cells, they were selected to compare cell death signaling. In both PFOS- and PFDA-treated cells, the selected apoptosis- and pyroptosis-related markers were not altered under the tested conditions. PFDA was associated with increases in phosphorylated RIP3 and phosphorylated MLKL, whereas PFOS increased MLKL expression without detectable RIP3 activation. Inhibition experiments further suggested that necroptosis-related signaling contributes, in part, to PFOS- and PFDA-induced endothelial injury in vascular endothelial cells. These findings suggest that PFAS-induced vascular endothelial injury depends on molecular structure and cell type, and may involve distinct necroptosis-related signaling patterns. However, it should be noted that the PFAS concentrations used in this study were higher than those typically detected in environmental and human exposure settings. Full article

Cardiovascular remodeling, encompassing vascular remodeling, myocardial remodeling, and fibrosis-associated tissue remodeling, underlies atherosclerosis, pulmonary hypertension, myocardial infarction, myocardial fibrosis, and other cardiovascular diseases. Its regulation has traditionally been studied through transcriptional, inflammatory, metabolic, mechanical, and intercellular signaling mechanisms. Recent advances in epitranscriptomics have identified N6-methyladenosine (m⁶A) RNA methylation as an additional post-transcriptional layer that interacts with microRNA (miRNA) pathways during cardiovascular disease progression. This review summarizes current evidence for m⁶A-miRNA crosstalk in cardiovascular remodeling, focusing on epitranscriptomic checkpoints that regulate miRNA fate, feedback-like regulatory circuits involving miRNAs and the m⁶A machinery, and cell-type-specific programs across endothelial cells, vascular smooth muscle cells, fibroblasts, and cardiomyocytes. We further discuss emerging analytical technologies and translational implications of this regulatory axis. Future studies should clarify causal mechanisms, cell-type and disease-stage specificity, and translational feasibility. Together, this multilayered framework provides a systems-level perspective on how RNA regulatory networks may shape pathological remodeling in cardiovascular disease. Full article

Endothelial progenitor cells (EPCs) constitute a cell population that enters the circulation during aerobic exercise and facilitates vascular function. In a similar action, hematopoietic progenitor cells (HPCs) are also released into circulation in response to exercise. Peripheral vascular dysfunction is frequently present in patients with heart failure. Whether acute interval exercise performed with high intensity induces EPC and HPC mobilization and affects microcirculation remains under investigation. The study population consisted of nineteen male patients with chronic heart failure (CHF) and eleven age-matched healthy individuals who underwent a high-intensity interval exercise session. Blood was drawn before, immediately after exercise, and 40 min after exercise to identify the numbers of circulating EPCs and HPCs by flow cytometry. Microcirculatory assessment was performed using near-infrared spectroscopy before and after exercise. Vascular endothelial growth factor (VEGF) change was also assessed before and after exercise in patients with CHF using flow cytometry. The interval exercise protocol revealed significant effects (p < 0.05) on EPC and HPC mobilization and systemic microcirculation (p < 0.05) in patients with CHF and healthy individuals. No significant differences were observed between patients with CHF and healthy individuals during interval exercise. VEGF did not reveal any changes immediately after interval exercise in CHF patients. Acute high-intensity interval training was associated with increased EPC and HPC mobilization and changes in microcirculation in patients with CHF and healthy individuals. Full article

Background/Objectives: Angiogenic T (Tang) cells support endothelial repair and vascular homeostasis. This cross-sectional study compared circulating Tang cell levels in young adults with T1DM vs. healthy controls, and assessed associations between Tang cells and continuous glucose monitoring (CGM) metrics. Methods: Sixty-five young adults with T1DM and 55 healthy controls were enrolled at the University of Campania “Luigi Vanvitelli,” Naples, Italy. Clinical and biochemical data were collected. Tang cells (CD3⁺CD31⁺CD184⁺) were quantified by flow cytometry as absolute counts and percentage of CD3⁺ T cells. In T1DM, CGM metrics from the preceding 14 days were analyzed, including time in range (TIR), time above range (TAR), and time below range (TBR). Results: Individuals with T1DM had higher fasting glucose and HbA1c than controls. Total CD3⁺ T cell counts were lower in T1DM. Tang cells were significantly reduced in T1DM both as absolute number and percentage (21% [10–31] vs. 48% [39–62]; p < 0.001). In multivariable analyses, Tang cell percentage was positively associated with TIR and inversely associated with HbA1c and TAR. Conclusions: Young adults with T1DM exhibit significantly reduced circulating Tang cells. Associations with CGM metrics support a link between real-world glucose control and endothelial vascular health. 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

The myocardium possesses one of the highest vascular densities in the body. The outermost wall layer of large and medium-sized vessels, the adventitia, forms a critical interface between the vasculature and the myocardium and serves as a reservoir for stem and progenitor cells capable of differentiating into all vascular wall lineages as well as innate immune cells, including macrophages. Current cardiac organoid models intrinsically develop networks of endothelial cords and small capillary-like structures that resemble cardiac microvessels. However, these microvessels mostly lack an adventitial compartment in vivo. Here, we present a potential alternative assembloid strategy that combines vascular segments from mouse and human origin with either cardiomyocytes or cardiac spheroids derived from human induced pluripotent stem cells, thereby incorporating large diameter vessels and the vascular adventitia into a cardiac tissue model. Within the assembloids, the myocardial component remained contractile and connected to the vascular adventitia, which displayed cellular sprouting toward the hiPSC-derived cardiac tissue. Immunostaining for vascular and immune markers revealed that the adventitia gave rise to endothelial sprouts and macrophage-like cells which integrated into the myocardial tissue. In summary, we present proof of concept for complex assembloids composed of vessel segments and human iPSC-derived cardiomyocytes which contain and maintain an in vivo-like adventitial compartment. We suggest this model may serve as a platform for investigating myocardial–stromal interactions, cardiac tissue repair, and functional remodeling under both physiological and pathological conditions. Furthermore, the incorporation of large-lumen vessel segments may enable future experimental perfusion, rendering the model particularly suitable for drug testing via intravascular delivery. Full article

Hydrogel scaffolds have emerged as instructive microenvironments for craniofacial tissue regeneration, moving beyond passive cell carriers toward platforms that regulate cell fate, vascularization, immune remodeling, and tissue-specific architecture. This review synthesizes hydrogel-associated strategies across dental pulp, periodontal ligament, gingival, bone marrow, jawbone, endothelial, oral mucosal, induced pluripotent stem cell (iPSC), extracellular vesicle (EV), exosome, secretome, and acellular systems. The evidence indicates that craniofacial hydrogel performance is governed by reciprocal interactions among biological source, scaffold composition, matrix mechanics, spatial architecture, mineral or ionic signaling, growth factor delivery, vesicle-mediated communication, and inflammatory niche modulation. Mineralized and ion-releasing hydrogels most consistently supported osteogenesis and bone repair, whereas extracellular matrix (ECM)-mimetic, peptide, collagen, fibrin, gelatin methacryloyl (GelMA), alginate, hyaluronic acid (HA), and chitosan-based systems enabled pulp–dentin, periodontal, peri-implant, oral mucosal, and soft-tissue reconstruction. Responsive, antimicrobial, antioxidant, conductive, and immunomodulatory hydrogels further expanded the field by targeting diseased microenvironments rather than regeneration alone. Despite strong preclinical evidence, translation remains limited by heterogeneity in scaffold formulations, biological sources, analytical endpoints, defect models, and long-term functional validation. Future progress will require standardized characterization, tissue-specific design criteria, clinically relevant large-animal models, scalable cell-free technologies, and integrated assessment of regeneration, immunity, vascularization, innervation, mechanics, and safety. Full article

Background/Objectives: Pediatric sepsis is increasingly recognized as a syndrome involving immune–vascular dysregulation. However, most pediatric biomarker studies focus on individual molecules rather than coordinated patterns of leukocyte–endothelial activation. This study aimed to evaluate whether children diagnosed with sepsis within 48 h of admission showed a coordinated soluble adhesion-molecule activation profile measured at enrollment. Methods: This prospective cohort study included 144 children aged 1–60 months with suspected infection enrolled at Dong Nai Children’s Hospital, Vietnam, from May 2021 to October 2022. Blood samples were collected at enrollment. Sepsis was classified according to the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria within 48 h of admission. Twelve soluble adhesion molecules were measured using a multiplex immunoassay. A composite adhesion activation score was derived by log2 transformation, z-score standardization, and averaging across the 12 markers. Principal component analysis (PCA) was used as an exploratory method to summarize the shared variation across the adhesion-molecule panel. C-reactive protein (CRP) was included as a routinely available inflammatory comparator. Results: Among 144 children, 32 (22.2%) were diagnosed with sepsis within 48 h of admission. Individual marker discrimination was strongest for L-selectin (area under the receiver operating characteristic curve [AUC] 0.883), followed by soluble vascular cell adhesion molecule-1 (sVCAM-1; AUC 0.855), intercellular adhesion molecule-3 (ICAM-3; AUC 0.838), P-selectin glycoprotein ligand-1 (PSGL-1; AUC 0.836), E-selectin (AUC 0.819), and intercellular adhesion molecule-2 (ICAM-2; AUC 0.819). CRP also differed between children with and without sepsis but had a lower AUC than the leading adhesion molecules in descriptive ROC analyses. The composite adhesion activation score was strongly associated with sepsis (odds ratio 7.95 per 1-standard deviation increase; 95% confidence interval 3.44–18.40; p < 0.001) and showed good discrimination (AUC 0.855; 95% confidence interval 0.776–0.931). The first principal component explained 70.0% of biomarker variance, consistent with coordinated elevation of correlated adhesion molecules. Conclusions: In this prospective Vietnamese pediatric cohort, children diagnosed with sepsis within 48 h of admission showed coordinated elevation of soluble adhesion molecules measured at enrollment. These findings support the biological relevance of leukocyte–endothelial activation in pediatric sepsis. However, the adhesion-molecule activation profile should be considered exploratory and hypothesis-generating, requiring external validation and further evaluation against simplified, clinically feasible biomarker approaches. Full article

Objectives: To investigate the clinicopathologic characteristics and molecular biomarkers of atypical vasoproliferative retinal tumor (VPRT) with hemangioblastoma-like histopathologic features and concomitant von Willebrand factor (VWF) abnormalities. Methods: A 48-year-old woman undergoing phacoemulsification and 25-gauge pars plana vitrectomy with tumor resection was evaluated. Histopathological findings and immunohistochemical study of the resected tumor were performed using CD34, α-smooth muscle actin (αSMA), and glial fibrillary acidic protein (GFAP) markers. Preoperative plasma and intraoperative vitreous fluid VWF antigen levels, as well as ristocetin cofactor activity, were quantified using latex immunoturbidimetry. Results: Ultra-widefield imaging and angiography demonstrated a peripheral retinal tumor with intense vascular leakage and surrounding capillary nonperfusion. Histopathology showed hyalinized vascular components supportive of VPRT, along with abundant CD34/α-SMA-positive microvessels and scant GFAP-positive glial cells. Notably, numerous foamy vacuolated poorly differentiated cells suggested mixed hemangioblastoma-like features. Preoperative plasma VWF antigen (182.6%) and ristocetin cofactor activity (147.7%) were elevated, and vitreous VWF antigen was successfully detected at a low but distinct level (7.7%).and suggests that VWF abnormalities in the plasma and vitreous may reflect endothelial activation and/or blood–retinal barrier disruption in a subset of vascularized retinal tumors. Conclusions: Our findings demonstrate that VPRT may exhibit mixed clinicopathologic features, including hemangioblastoma-like components, which underscores the necessity of immunohistochemical assessment for definitive diagnosis. Furthermore, the quantification of VWF abnormalities in the plasma and vitreous suggests that VWF serves as a potential biomarker reflecting endothelial activation and/or blood–retinal barrier disruption in vascularized retinal tumors. Full article

Ischemic stroke elicits a rapid and sustained innate immune response that critically contributes to blood–brain barrier (BBB) breakdown and secondary neuronal injury. Among the cellular mediators involved, neutrophil extracellular traps (NETs) have emerged as potent effectors of neurovascular damage. However, the regulatory mechanisms governing NET formation and their prolonged impact on BBB integrity remain incompletely understood. Increasing evidence indicates that NET formation is an epigenetically regulated process, requiring chromatin remodeling, histone modifications, DNA methylation changes and non-coding RNA-mediated control within neutrophils under ischemic conditions. These epigenetic events license the extrusion of DNA–histone–enzyme complexes that directly injure endothelial cells, degrade tight junction proteins, activate innate immune signaling pathways and amplify neuroinflammatory cascades at the neurovascular unit. Moreover, NET-derived chromatin and associated mediators can induce transcriptional and epigenetic alterations in BBB cells, thereby sustaining barrier permeability and impairing vascular repair mechanisms. In this review, we synthesize current knowledge on the epigenetic regulation of NET formation and delineate how epigenetically regulated NETs function as key disruptors of BBB integrity in ischemic stroke. Understanding this NETosis–epigenetics–BBB axis may uncover novel therapeutic strategies aimed at preserving neurovascular integrity and limiting post-stroke brain injury. Full article