Search Results (3,720)

Peripheral arterial disease (PAD) is estimated to affect at least 10 million people in the United States and over 200 million individuals worldwide. The clinical manifestations of PAD range from impaired mobility and pain with activity to chronic limb-threatening ischemia with risk of eventual tissue loss. Despite the significant global prevalence and debilitating consequences of the disease, non-option patients remain largely undertreated. Recognizing that ECs are well-known for their therapeutic role in enhancing perfusion and neovascularization in mouse models of critical limb ischemia, we hypothesize that a synergy of ECs with SMCs may achieve better recovery of perfusion and neovascularization than ECs or SMCs alone. In this study, we compared the therapeutic efficacy of hiPSC-ECs, hiPSC-SMCs, and hiPSC-ECs + hiPSC-SMCs for the treatment of critical limb disease using a NOD-SCID mouse model of hind limb ischemia (HLI). A total of 1 × 10⁶ hiPSC-ECs, 1 × 10⁶ hiPSC-SMCs, or 0.5 × 10⁶ hiPSC-ECs + 0.5 × 10⁶ hiPSC-SMCs were intramuscularly injected into the ischemic limb of the mouse on day 3 after HLI induction. Laser Doppler was recorded on day 0 before, days 3 (i.e., before cell administration) and 31 after HLI induction. Compared with only basal medium injection, hiPSC-ECs alone most effectively improved perfusion (63.8% after normalized non-ischemic limb, p < 0.001) and neovascularization (total vessel density = 180.9/magnification, p < 0.001) followed by co-administration of hiPSC-ECs + hiPSC-SMCs (perfusion = 59%, p = 0.008 and total vessel density = 170.5, p = 0.002) compared with basal medium injection (perfusion = 39.7% and total vessel density = 107.2), while hiPSC-SMCs administration achieved mild to moderate improvement (perfusion = 48.9% and total vessel density = 159.5, p = 0.01). When profiles of secreted growth factors or cytokines were determined using a protein array, 34 growth factors or cytokines involved in angiogenesis were highly enriched (at least >50% increase) in a hiPSC-ECs conditioned medium, including basic fibroblast growth factor and vascular endothelial growth factor, while there were 14 in hiPSC-SMCs conditioned medium. In conclusion, our results demonstrate that hiPSC-ECs alone most effectively improved perfusion and neovascularization, followed by co-administration of hiPSC-ECs + hiPSC-SMCs, which may be due to the abundance of growth factors and cytokines secreted by hiPSC-ECs. Future studies are warranted to evaluate the therapeutic efficacy of hiPSC-EC and hiPSC-SMC co-transplantation in aged animals with metabolic and cardiovascular comorbidities. Full article

Antiphospholipid syndrome is a systemic autoimmune disease characterized by elevated circulating antiphospholipid antibodies and a predisposition to recurrent venous and arterial thrombosis. The underlying pathophysiology of antiphospholipid syndrome remains under active investigation, with endothelial dysfunction recognized as a key contributor to vascular complications. In this study, we showed that serum from antiphospholipid syndrome patients differentially affects distinct endothelial cell types, leading to variations in migration and angiogenic behavior. Using human umbilical vein endothelial cells and human microvascular endothelial cells, we assessed the biological response to serum exposure. Treatment with antiphospholipid syndrome serum was associated with an enhanced angiogenic phenotype in venous endothelium, with a significant increase in two of the four tubulogenesis parameters assessed and a trend towards increased migration, while microvascular endothelium remained largely unaffected. Consistently, metalloproteinase-9 activity was upregulated, with these effects being more pronounced in venous compared to microvascular endothelium. Moreover, caspase-3 activity remained unchanged, suggesting that caspase-3-dependent apoptosis is unlikely to be a major contributor to the endothelial response observed under these conditions. These results enhance our understanding of the pathogenesis and highlight the distinct endothelial responses to the antiphospholipid environment. Further investigation into the underlying mechanisms may facilitate the development of targeted therapeutic strategies to mitigate vascular complications. Full article

Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, yet their polymer-specific effects on endothelial cells remain poorly understood, particularly at the placental and fetal level. We compared cadmium selenide quantum dot-labelled polypropylene (PP) and polyvinyl chloride (PVC) model nanoplastics (NPs) in human umbilical vein endothelial cells (HUVECs) using particle characterization, MTT assays, flow cytometry, confocal microscopy, apoptosis analysis, and synchrotron nano-X-ray fluorescence imaging. PP nanoplastics caused an early reduction in metabolic activity, showed the strongest cell-associated fluorescence, and produced the greatest increase in membrane permeability and late apoptotic/necrotic populations. PVC nanoplastics displayed a more punctate distribution with greater overlap with membrane-associated regions and induced a stronger increase in LC3B-positive vesicular structures. Nano-XRF detected Cd-enriched signals associated with the labelled particles and a polymer-specific Cd–Cl spatial association in PVC-exposed cells. Sulfur mapping further revealed localized sulfur-poor regions along the cell periphery in exposed cells, suggesting localized remodeling of peripheral membranes. These findings indicate that PP and PVC NPs interact differently with endothelial cells and elicit distinct structural and functional responses. Polymer composition should therefore be considered when assessing the vascular and prenatal effects of MNP exposure. Full article

Atherosclerosis is a complex, multifactorial disease and the leading underlying cause of cardiovascular morbidity and mortality worldwide. Beyond traditional risk factors, growing evidence highlights the critical role of environmental exposures in modulating atherogenesis. In real-world scenarios, individuals are exposed to complex mixtures of contaminants, including particulate matter, toxic metals, pesticides, polycyclic aromatic hydrocarbons, and endocrine-disrupting chemicals. These combined exposures may exert additive, synergistic or antagonistic effects, resulting in biological responses that cannot always be predicted from single-agent exposures. At the cellular and molecular level, both chemical mixtures and environmental co-exposures converge on key pathogenic pathways, including oxidative stress, endothelial dysfunction, chronic inflammation, and lipid dysregulation. These processes may favor monocyte recruitment, foam cell formation, vascular smooth muscle cell remodeling, and plaque instability. Moreover, cumulative exposures are associated with epigenetic alterations, such as dysregulation of DNA methylation and non-coding expression patterns, which may influence long-term susceptibility to atherosclerosis. This structured narrative review synthesizes evidence from 37 studies investigating the cellular and molecular mechanisms underlying the impact of environmental mixtures and multipollutant co-exposures on atherosclerosis. By integrating evidence from epidemiological, toxicological, experimental, bioinformatics and multi-omics studies, while recognizing the predominantly associative nature of the available human evidence, we highlight emerging mechanistic insights and discuss the relevance of mixture-based approaches for improving risk assessment and informing future preventive strategies. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) poses therapeutic challenges because of oxidative stress, blood–brain barrier disruption, and neuronal apoptosis, limiting current treatments. Paeoniflorin (PF) from Paeonia lactiflora has neuroprotective potential, but its multi-target mechanisms remain unclear. This study investigated the role and mechanisms of PF in CIRI, focusing on neuron–endothelial crosstalk. Methods: Oxygen–glucose deprivation/reoxygenation (OGD/R) models were established using SH-SY5Y (human neuroblastoma) and HCMEC/D3 cells (human cerebral microvascular endothelial). Network pharmacology was used to predict potential PF targets and pathways. RNA sequencing, molecular docking, and molecular dynamics simulation were performed to screen and evaluate PF binding characteristics with key targets, and MTT, flow cytometry, Western blotting, and co-cultures were employed to detect paracrine interactions. Results: Network pharmacology and transcriptomics identified VEGF/PI3K-AKT/mTOR pathway enrichment. Molecular docking confirmed stable PF binding to VEGF-A (−8.4 kcal/mol), AKT (−5.5 kcal/mol), and mTOR (−9.6 kcal/mol). PF (10–80 μM) showed no cytotoxicity and reduced OGD/R injury in a concentration-dependent manner (maximal at 40 μM). PF activated VEGF/PI3K-AKT/mTOR signaling, reducing apoptosis by 57% (SH-SY5Y) and 33% (HCMEC/D3); PI3K inhibitor LY294002 abolished these effects. PF-treated HCMEC/D3-conditioned media enhanced OGD/R neuronal viability, verifying paracrine crosstalk. Conclusions: PF alleviated CIRI by directly protecting neurons and indirectly modulating neuron–endothelial crosstalk through VEGF/PI3K-AKT/mTOR activation, supporting its multi-target therapeutic potential. Full article

Diabetes mellitus induces endothelial dysfunction and oxidative stress, contributing to the development of vascular complications. Although metformin exerts well-established vasculoprotective and antioxidant effects, the molecular mechanisms underlying these actions remain incompletely understood. Novel miR-1133 was previously identified as a metformin-responsive putative microRNA (miRNA), and bioinformatic analysis identified PIK3CA as a biologically plausible candidate target for further investigation. This study investigated the functional significance of novel miR-1133 in the antioxidant effects of metformin in hyperglycemia-induced human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to normal glucose (5.5 mmol/L), hyperglycemia (33.3 mmol/L), or hyperglycemia supplemented with metformin (10 μM) for 24 h. Metformin-treated hyperglycemic HUVECs were subsequently transfected with a novel miR-1133 mimic during continued hyperglycemic and metformin exposure. PIK3CA expression and oxidative stress markers, including reactive oxygen species (ROS), superoxide dismutase (SOD), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), were evaluated. Hyperglycemia increased novel miR-1133 expression, whereas metformin reduced its expression. Metformin treatment was associated with increased PIK3CA mRNA and protein expression, reduced ROS and 8-OHdG levels, and increased SOD expression and activity. Novel miR-1133 mimic transfection was associated with reduced PIK3CA expression, increased ROS and 8-OHdG levels, and decreased SOD expression and activity compared with the corresponding transfection control. Collectively, these findings demonstrate that metformin attenuates oxidative stress in hyperglycemia-induced endothelial cells and overall provide the first functional characterization of novel miR-1133. The reciprocal changes in PIK3CA expression and oxidative stress observed following novel miR-1133 mimic transfection suggest that novel miR-1133 may represent a candidate mediator of the endothelial antioxidant responses associated with metformin. Further studies are required to validate the direct interaction between novel miR-1133 and PIK3CA and to elucidate the underlying molecular mechanisms. Full article

Periodontal and alveolar bone regeneration requires coordinated angiogenic and osteogenic responses supported by biomimetic scaffolds. This study compared three-dimensional bioprinted hydroxyapatite–acrylated palm olein (3D-HA–APO) scaffold formulations containing 5%, 7% and 10% (w/v) hydroxyapatite (HA), designated F1, F2 and F3, respectively. Human umbilical vein endothelial cells were cultured on the scaffolds, and background-corrected soluble vascular endothelial growth factor (VEGF) concentrations in culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). Angiogenic-related responses of human periodontal ligament stem cells were assessed by VEGF and cluster of differentiation 31 (CD31) immunofluorescence after endothelial induction, while alkaline phosphatase (ALP) activity in construct lysates was used as an indicator of early osteogenic activity. Soluble VEGF concentrations increased from F1 to F3, with significant differences between all formulations. VEGF-associated signal proportions differed among formulations, with F3 significantly higher than F1. CD31-associated signal proportions increased progressively from F1 to F3, with significant differences between all formulation pairs. ALP activity increased over time in all scaffold groups, and F3 generally showed the highest activity from Day 4 onwards. Overall, F3 showed the most favourable formulation-level profile across the selected angiogenic-related and early osteogenic outcomes. Full article

Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of Wharton’s jelly-derived MSC secretome (WJ-MSCsec) on human endometrial stromal cells (EnSCs) and endothelial cells in vitro. Methods: WJ-MSCs were isolated from umbilical cord tissue, characterized, and cultured under serum-free conditions. The concentrated secretome was analyzed using a human angiogenesis proteome array. EnSCs were isolated from endometrial biopsies. EnSC proliferation and migration in the presence of WJ-MSCsec were assessed using CCK-8 and scratch wound-healing assays. Pro-angiogenic activity of WJ-MSCsec was evaluated using a Matrigel tube formation assay with human umbilical vein endothelial cells (HUVECs). Results: Proteomic analysis of WJ-MSCsec revealed the presence of angiogenic, mitogenic, immunomodulatory, and chemotactic factors. Treatment with WJ-MSCsec significantly enhanced EnSC proliferation and accelerated wound closure. Furthermore, WJ-MSCsec markedly promoted endothelial tube formation, increasing total tube length, junction number, and mesh formation. Conclusions: WJ-MSCsec stimulates EnSC proliferation and migration while enhancing angiogenesis in vitro. WJ-MSCsec represents a promising cell-free therapeutic strategy for endometrial regeneration and reproductive disorders associated with impaired endometrial function. Full article

Gene inactivation in model organisms has identified numerous genes and signaling pathways involved in mammalian cardiac outflow tract (OFT) development. Human genetics data have implicated the VEGFR3 gene in OFT development, but when and where it is required is unknown. In this study we determined the sensitivity of the developing murine heart to reduced Vegfr3 gene dosage, and we tested whether its requirement is dependent upon TBX1, a known regulator of Vegfr3 expression in cardiac and lymphatic endothelial cells. We found that in the mouse, a single copy of the Vegfr3 gene was sufficient for normal heart development in most cases. Mutation of a single copy of the Tbx1 gene greatly enhanced the sensitivity of heart development to Vegfr3 dosage reduction and led to the formation of cardiac defects. In addition, deletion of Vegfr3 in the Tbx1 expression domain also led to severe cardiac OFT abnormalities. We used RNAscope to reveal the location of Vegfr3 and Tbx1 transcripts in midterm mouse embryos. This revealed co-localization of these transcripts in the endothelium of the aortic sac, caudal pharyngeal arch arteries and proximal OFT, suggesting that these are potential sites of genetic interaction between Vegfr3 and Tbx1 that are critical for murine heart development. Full article

Background: Hantavirus pulmonary syndrome (HPS), also designated hantavirus cardiopulmonary syndrome, is caused by New World hantaviruses, principally Sin Nombre virus in North America and Andes virus in South America. The syndrome is characterized by rapidly progressive noncardiogenic pulmonary edema and myocardial depression, with case fatality rates of 25% to 40%. A 2026 outbreak aboard an expedition cruise ship in the South Atlantic, comprising 13 cases and three deaths, confirmed that Andes virus can be transmitted between humans in a confined setting remote from the rodent reservoir. Methods: Virological, pathophysiological, clinical, and therapeutic aspects of HPS were reviewed, with particular emphasis on cardiopulmonary mechanisms. Sources were identified through PubMed, Scopus, and Google Scholar, with priority given to original research articles, clinical series, and controlled trials published through 2025. Literature published in English and Spanish was included. Results: Pathogenic hantaviruses enter endothelial cells and platelets via αvβ3 integrins, disrupting the VEGF-VEGFR2 signaling axis and rendering endothelial cells hypersensitive to physiological VEGF concentrations. Expansion of CD8+ T cells and activated macrophages releases TNF-alpha, IFN-gamma, and nitric oxide, amplifying microvascular permeability and contributing to myocardial depression. Autopsy studies demonstrate direct hantaviral myocarditis with viral antigen in cardiac endothelium and interstitial macrophages. Transpulmonary thermodilution confirms simultaneous hypovolemia, reduced global ejection fraction, and elevated extravascular lung water. Because the incubation period is long and the cardiopulmonary phase is substantially immune-mediated, seroconversion precedes rather than follows clinical deterioration, which preserves the diagnostic utility of IgM serology in a disease that can kill within 48 h. VA-ECMO initiated at the first signs of cardiopulmonary decompensation has reported survival rates approaching 80% in selected experienced centers. No antiviral has demonstrated efficacy in controlled trials during the cardiopulmonary phase, and no licensed vaccine exists. Conclusions: HPS produces a mixed shock state through increased microvascular permeability, T cell-mediated immunopathology, and direct myocarditis. Management follows a stepwise algorithm: suspected HPS triggers immediate complete blood count with peripheral blood smear and concurrent hantavirus IgM serology and RT-PCR, followed by ICU admission, conservative fluid resuscitation guided by transpulmonary thermodilution, and early contact with an ECMO-capable center at the first sign of rising lactate, falling cardiac index, refractory shock, arrhythmia, or rapid oxygenation failure. Full article

Accumulation of senescent endothelial cells (ECs) accelerates atherosclerosis, yet the molecular orchestrators linking metabolic dysregulation to epigenetic reprogramming during EC senescence remain elusive. Here, we investigated the specific role of Myeloid cell leukemia 1 (MCL1) in endothelial senescence and atherogenesis. Through integrative bioinformatics, MCL1 was identified as a candidate senescence regulator. MCL1 expression was validated in human carotid atherosclerotic plaques, ApoE^−/− mice, and multiple EC senescence models, primarily HRAS^G12V-induced senescent human umbilical vein endothelial cells (HUVECs). Loss- and gain-of-function assays were performed in HUVECs. Underlying metabolic and epigenetic mechanisms were explored using Seahorse extracellular flux analysis, lactate measurements, Co-IP and CUT&Tag sequencing. In vivo therapeutic potential was evaluated via AAV-mediated MCL1 knockdown in high-fat diet-fed ApoE^−/− mice. MCL1 expression was significantly upregulated in atherosclerotic plaques and senescent ECs. Functionally, MCL1 knockdown attenuated senescence markers (SA-β-gal, P21), suppressed the senescence-associated secretory phenotype (SASP), and restored cell proliferation, whereas MCL1 overexpression exacerbated EC senescence. Mechanistically, MCL1 promoted glycolytic reprogramming and intracellular lactate accumulation. This metabolic byproduct served as an epigenetic substrate for histone H4K12 lactylation (H4K12la), which specifically enriched at the CDKN1A (P21) promoter, correlating with its transcription. In vivo, AAV-mediated MCL1 silencing effectively reduced vascular H4K12la levels, alleviated vascular senescence, and substantially constrained atherosclerotic lesion areas. Our findings identify MCL1 as a pivotal regulator of endothelial senescence and atherosclerosis, operating through a metabolic-\–epigenetic mechanism involving glycolytic reprogramming, lactate accumulation, and H4K12la-associated P21 upregulation. These findings suggest that targeting the MCL1-associated pathway may represent a potential therapeutic strategy for atherosclerosis. Full article

Donor-derived cell-free DNA (dd-cfDNA) is an emerging non-invasive biomarker of kidney allograft injury. Elevated dd-cfDNA has been associated with acute rejection, particularly antibody-mediated rejection; however, dd-cfDNA reflects graft-derived tissue injury rather than a specific alloimmune mechanism. Its interpretation may therefore be challenging in conditions characterized by endothelial and microvascular injury, such as atypical hemolytic uremic syndrome (aHUS). This retrospective observational study included 14 kidney transplant recipients who underwent their first kidney transplantation at Wroclaw Medical University between April and December 2022. Twelve recipients without aHUS and two recipients with aHUS were assessed at day 7 (D7), day 14 (D14), month 1 (M1), and month 2 (M2). Protocol biopsies were not systematically performed. In recipients without aHUS, median %dd-cfDNA declined from 0.72% (range, 0.26–2.33%) at D7 to 0.12% (range, 0.05–0.34%) at M2. In the two recipients with aHUS, values remained near or above 1% through M1 and declined at M2. No donor-specific antibodies against human leukocyte antigens (HLA) or clinically documented rejection occurred. Exploratory analyses did not identify a statistically significant association between %dd-cfDNA and serum creatinine (Spearman rho = 0.09, p = 0.541). These recipient-level observations suggest that early dd-cfDNA kinetics in the two recipients with aHUS differed from the declining pattern in the small comparison cohort, but they do not establish a group-level difference. Because protocol biopsies were not systematically performed, subclinical rejection could not be excluded. The findings should be considered hypothesis-generating and support cautious interpretation of universal dd-cfDNA thresholds in aHUS. Full article

Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by intracranial arterial stenosis and abnormal collateral vessel formation. The molecular mechanisms by which extracellular vesicle (EV)-derived microRNAs contribute to endothelial dysfunction remain poorly understood. We investigated whether circulating extracellular vesicle-derived microRNAs (EV-miRNAs) contribute to endothelial dysfunction and serve as functional mediators of MMD pathogenesis. Plasma EV-miRNA profiles were compared among patients with MMD, intracranial atherosclerosis (ICAS), and healthy controls, and differentially expressed EV-miRNAs were validated in an independent cohort. Functional studies were performed in human umbilical vein endothelial cells and patient-derived induced pluripotent stem cell-derived endothelial cells. Three EV-miRNAs were significantly upregulated in MMD, among which miR-558 showed the strongest diagnostic performance. miR-558 overexpression impaired endothelial tube formation and proliferation, whereas its inhibition enhanced angiogenic activity. Mechanistically, HMGB2 was identified as a direct target of miR-558, and miR-558 overexpression reduced HMGB2 protein expression. Patient-derived endothelial cells recapitulated increased miR-558 expression, reduced HMGB2 levels, and impaired angiogenic capacity. These findings identify circulating EV-miR-558 a potential biomarker and show that miR-558 suppresses HMGB2 and impairs endothelial angiogenesis in adult MMD, suggesting that the EV-miR-558/HMGB2 pathway represents a potential mechanism underlying endothelial dysfunction and therapeutic target for MMD. Full article

Trauma with hemorrhagic shock causes about 2.3 million deaths yearly worldwide. Improved hemostatic management has shifted the relative distribution of mortality, leaving multiorgan failure (MOF) as a leading cause of death. Clinical observations suggest that the evolutionarily ancient and well-conserved sympathetic system and the microvascular endothelium are involved, and the experimental evidence is reviewed here. The analyzed clinical studies, human endothelial cell (EC) culture, and animal model-based experiments delineate how excess catecholamine levels increase endothelial cell reactive oxygen species production, causing glycocalyx damage and thrombomodulin cleavage. This leads to a prothrombotic EC surface, resulting in coagulation activation and thrombus formation that leaves tissues prone to hypoxia. Excess catecholamines also increase endothelial barrier permeability, leading to fluid extravasation, elevated tissue pressure, and hypoxia. The reviewed experimental data support, but do not yet prove, dysregulated sympathetic activation’s critical contribution to the development of shock-induced endotheliopathy prone to tissue hypoxia and, ultimately, death from coagulopathy, loss of immune competence, and MOF, as observed clinically in shocked trauma patients. Due to the physiological differences between humans and model organisms, and EC culture growth conditions, some molecular mechanisms require further investigation through clinical studies and targeted experiments. Full article

Vasculogenesis, the de novo formation of blood vessels from endothelial progenitor cells, is increasingly recognized as a critical contributor to tumor vascularization, complementing classical angiogenesis and promoting cancer progression, metastasis, therapeutic resistance, and disease recurrence. This narrative review aims to provide a comprehensive overview of the molecular mechanisms governing vasculogenesis across human malignancies and to discuss their translational relevance for targeted cancer therapy. This is a narrative, mechanistically oriented review rather than a systematic review or meta-analysis. The literature was searched in PubMed, Scopus, and Google Scholar, with the primary search covering publications from January 2010 to February 2026, while seminal earlier studies were included when they established fundamental concepts in vascular biology. Search terms included combinations of “vasculogenesis”, “tumor vasculogenesis”, “angiogenesis”, “endothelial progenitor cells”, “vascular remodeling”, “VEGF”, “HIF-1α”, “Notch”, “Wnt”, “PI3K/AKT”, “TGF-β”, “EndMT”, “mechanotransduction”, “non-coding RNAs”, “tumor microenvironment”, and “cancer”. Evidence was qualitatively appraised and synthesized according to mechanistic relevance and consistency across experimental and clinical studies. The reviewed literature highlights the complex interplay between developmental signaling pathways, endothelial plasticity, mechanical cues, inflammatory mediators, and non-coding RNAs in regulating tumor vasculogenesis. Collectively, these findings suggest that targeting vasculogenesis-related pathways may complement existing anti-angiogenic therapies and represent a promising strategy for improving precision oncology and overcoming treatment resistance. Full article