Search Results (1,270)

N-acetylcysteine (NAC) is a thiol-containing molecule with antioxidant, anti-inflammatory, antimicrobial, and cytoprotective properties that has increasingly been incorporated into hydrogel-based biomaterials. This systematic review evaluates the strategies used to integrate NAC into hydrogels and examines their effects on material properties, controlled release, biocompatibility, and therapeutic activity. The review was conducted according to the PRISMA guidelines using Scopus, PubMed, Web of Science, and SciFinder to identify English-language articles published between 2000 and 2025. Seventy-three studies met the eligibility criteria of this review. NAC has been employed as a physically loaded therapeutic agent, covalently conjugated polymer modifier, contributor to hydrogel crosslinking, metal-coordination ligand, and compound incorporated into nano- and microparticulate carriers dispersed in hydrogel. These approaches enable the modulation of gelation, swelling, adhesion, degradation, and drug-release kinetics. NAC-containing hydrogels have demonstrated robust antioxidant, antimicrobial, antibiofilm, anti-inflammatory, angiogenic, and tissue-regenerative properties in various in vitro and in vivo models, underscoring their potential for advanced biomaterial applications. Release profiles varied from rapid stimulus-responsive delivery to sustained release over several days, depending on the network architecture and the NAC–matrix interactions. However, comparisons among studies were limited by the heterogeneous formulations, release conditions, biological models, and outcome measures. Standardized physicochemical characterization, NAC stability assessment, dose–response evaluation, and rigorous preclinical validation are required to support the translation of NAC-based hydrogels into biomedical applications. We hope that this review will help scientists and innovation centers understand the potential of the NAC-containing hydrogel biomaterials discussed in this study, as well as the opportunities and demands for additional research in this field. Full article

Fracture healing depends on coordinated osteogenesis and restoration of the vascular microenvironment. Endothelial cells support skeletal repair through angiogenesis, tissue perfusion and angiocrine signaling that regulates osteoprogenitor recruitment and differentiation. This narrative review examines endothelial dysfunction (ED) as a potential systemic contributor to impaired fracture healing by integrating evidence from vascular biology, experimental models and clinical studies. ED is characterized by reduced nitric oxide (NO) bioavailability, oxidative stress, inflammation and impaired vascular repair. These changes may disrupt angiogenic–osteogenic coupling through altered hypoxia-inducible factor 1-alpha subunit (HIF-1α)/vascular endothelial growth factor (VEGF) signaling, endothelial Notch activity, platelet-derived growth factor (PDGF)-mediated vascular remodeling and endothelial progenitor cell (EPC) mobilization. Conditions associated with endothelial dysfunction, including diabetes, aging, chronic kidney disease (CKD), smoking, obesity and chronic inflammatory disease, are also linked to delayed union, nonunion and poorer orthopedic outcomes. Cardiovascular disease and perioperative cardiovascular instability may further impair perfusion and physiological reserve during repair. However, the available evidence is predominantly experimental or observational, and direct causal evidence in fracture patients remains limited. Prospective studies combining standardized endothelial assessments with fracture-healing outcomes are needed to clarify clinical relevance and identify potential therapeutic targets. Full article

Background/Objectives: Hypertensive disorders of pregnancy (HDPs) such as preeclampsia are associated with adverse maternal and perinatal outcomes and related to high soluble fms-like tyrosine kinase-1 (sFlt-1) levels and low placental growth factor (PlGF) levels. While these biomarkers are used for predicting and diagnosing preeclampsia, their impact on postnatal neonatal nutritional management, growth, and body composition is not well-established. Therefore, we aimed to evaluate the association between maternal angiogenic markers, neonatal growth, and body composition. Methods: This study represents a secondary analysis of a prospective cohort study conducted at the Medical University of Vienna. Women with HDP were included in the analysis, and infants were stratified by gestational age at birth into preterm (<37 weeks of gestation) and term (≥37 weeks of gestation) groups. Maternal angiogenic markers were routinely measured at the time when HDP was first suspected, and neonatal body composition was assessed at term-equivalent age. Results: A total of 335 infants were screened, 94 of which (preterm: n = 72; term: n = 22) were included. Higher sFlt-1/PlGF ratios were significantly correlated with lower fat-free mass (FFM) z-scores (rs = −0.408; p = 0.004), but not with fat mass (FM) z-scores (p = 0.21), weight (p = 0.19), length (p = 0.31), or head circumference z-scores (p = 0.32) in preterm infants. In a linear regression model adjusted for potential neonatal confounders, higher sFlt-1/PlGF ratios were independently and significantly associated with lower FFM in preterm infants (median: −0.10, 95% CI: −0.2, 0.00; p = 0.036). In term infants, sFlt-1/PLGF ratios were not significantly correlated with FFM (p = 0.86), FM z-scores (p = 0.41), weight (p = 0.10), length (p = 0.12), or head circumference z-scores (p = 0.2). Conclusions: These findings suggest that the sFlt-1/PLGF ratio is not only a well-established marker of HDP severity during pregnancy but may also be associated with adverse effects on body composition in preterm infants, particularly in fat-free mass (FFM). Full article

Melanoma dissemination depends on tumor cell plasticity, extracellular matrix remodeling, and adaptive signaling pathways that promote survival, migration, invasion, and therapeutic resistance. In this study, we investigated the antitumor effects of the plant-derived Kunitz-type protease inhibitor EcTI using both in vitro B16F10-Nex2 melanoma cells and an in vivo murine melanoma model, focusing on adhesion-dependent signaling, autophagy, mitochondrial dysfunction, and regulated cell death. EcTI was efficiently internalized by melanoma cells and showed partial colocalization with lysosomal and mitochondrial compartments, suggesting intracellular trafficking toward these organelles. Treatment reduced cell adhesion to extracellular matrix proteins, particularly fibronectin and laminin, and inhibited migration, invasion, and angiogenic signaling. These effects were associated with modulation of the adhesion-dependent FAK/Src/ERK signaling axis and decreased MMP-9 activity. EcTI also disrupted autophagy, as indicated by accumulation of acidic vesicular organelles, increased LC3-II levels, and modulation of ULK1, Ambra1, and Beclin-1 signaling. In parallel, EcTI induced mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential, intracellular Ca²⁺ dysregulation, and increased reactive oxygen species production. These alterations triggered regulated cell death involving apoptotic and necroptosis-like mechanisms. Importantly, EcTI significantly suppressed tumor growth in vivo without detectable systemic toxicity and modulated inflammatory mediators associated with tumor progression. Overall, these findings demonstrate that EcTI exerts broad antitumor activity by modulating multiple signaling pathways associated with melanoma progression and represents a promising therapeutic candidate for melanoma treatment. 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

Background: Endometriosis is a chronic estrogen-dependent disease characterized by the presence of endometrial-like tissue outside the uterine cavity. Its pathogenesis involves interactions between inflammatory, angiogenic, hormonal, oxidative stress-related, and cell survival-associated pathways, contributing to lesion development and persistence. Current treatment options are often limited by adverse effects, incomplete symptom control, and high recurrence rates. Methods: This integrative review summarizes the molecular mechanisms involved in endometriosis and the potential role of natural bioactive compounds in their modulation. A literature search was conducted using PubMed, Scopus, and Web of Science, and evidence from experimental, animal, and clinical studies was reviewed. Results: Natural compounds such as curcumin, resveratrol, quercetin, EGCG (epigallocatechin-3 gallate) and genistein have been reported to modulate multiple pathways involved in endometriosis. Their biological activity includes modulation of inflammatory signaling, angiogenesis, estrogen-dependent processes, epithelial–mesenchymal transition, oxidative stress, and apoptosis. While some compounds influence several interconnected pathways, others appear to exert more selective effects. Conclusions: The findings summarized in this review suggest that natural bioactive compounds may influence several interconnected mechanisms involved in endometriosis. Although clinical evidence remains limited, these compounds warrant further investigation as potential adjuncts to current therapeutic approaches. Full article

Background/Objectives: This study engineered and evaluated a targeted, folate-functionalized chitosan nanoparticle (CS-FA NP) delivery system to enhance the therapeutic efficacy of standard quercetin and Coriandrum sativum seed extract against breast cancer. Methods: Phytochemical profiling confirmed a 14% crude yield for the methanolic extract, with gas chromatography–mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) identifying quercetin as the principal bioactive agent. The synthesized CS-FA NPs exhibited a core size of 7–20 nm, an average hydrodynamic diameter of 150–160 nm, a stable zeta potential of −55 mV, and high encapsulation efficiencies (87.2% for quercetin and 80.5% for coriander). Kinetic assessments confirmed a biphasic, diffusion-controlled release matching Higuchi matrix kinetics. Anticancer activity was evaluated in vitro using MTT cytotoxicity, Annexin V-FITC/PI apoptosis analysis, RT-qPCR, and ex vivo rat aortic ring assays, followed by validation in a syngeneic 4T1 mammary tumor mouse model. Results: In vitro, folate-receptor-targeted quercetin nanoparticles (T4) demonstrated superior, selective cytotoxicity, particularly against triple-negative MDA-MB-231 cells, while sparing normal fibroblasts. Annexin V-FITC/PI apoptosis profiling and ex vivo aortic ring assays revealed profound, cell-line-dependent programmed cell death and up to 90% inhibition of microvessel sprout outgrowth. Mechanistically, RT-qPCR verified that nano-formulations induced complete transcriptional silencing of NANOG, MMP-1, VEGFA, TSPAN8, TWIST, EMMPRIN, and CDK1, alongside marked upregulation of P27^KIP1 and P21^CIP1. In vivo, these nano-formulations successfully improved tumor-associated pathological features, reduced aggressive tumor spindle-cell proliferation, and suppressed elevated serum CA15-3 and arginase biomarkers. Conclusions: Folate-functionalized chitosan nano-formulations significantly enhanced the anticancer efficacy of quercetin and Coriandrum sativum seed extract through improved targeted delivery, potent antiproliferative, anti-angiogenic, and pro-apoptotic activities, together with favorable modulation of multiple molecular pathways associated with breast cancer progression. These findings support their potential as promising targeted nanotherapeutic strategies for breast cancer treatment. Full article

Oral submucous fibrosis (OSMF) is a chronic, progressive fibrotic disorder with significant malignant potential, and limited effective treatments due to an incomplete understanding of its underlying molecular mechanisms. This narrative review synthesizes current evidence on the key molecular networks involved in OSMF pathogenesis, highlighting the central role of the TGF-β1/Smad, CTGF, and COL1A1 pathways in maintaining fibroblast activation, supporting myofibroblast activity, and promoting pathological collagen accumulation. It also integrates recent findings on how profibrotic signaling interacts with important angiogenic and epithelial growth factors such as VEGF, FGF, and EGF, creating a stage-dependent fibrotic microenvironment. In early OSMF, increased angiogenic signaling, especially through the VEGF/PI3K–Akt pathway, helps maintain blood supply. However, as the disease progresses, TGF-β-induced pathways become dominant, leading to vascular rarefaction, tissue hypoxia, epithelial instability and worsening fibrosis that increases the risk of malignant transformation. By critically appraising molecular, cellular, and translational studies, this review identifies key pathways linking fibrosis, angiogenesis, and epithelial changes in OSMF. It suggests that stage-specific and combined targeting of TGF-β1, CTGF, COL1A1, along with angiogenic and epithelial pathways, may help reverse fibrosis, restore normal tissue perfusion, reduce cancer risk, and support the development of better therapies and biomarkers beyond symptom relief. Full article

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Reconstructive surgery still faces various challenges when dealing with the reconstruction of complex skin defects, regardless of their origin (e.g., trauma, burns). Split-thickness autologous skin grafts remain the gold standard; however, this technique comes with several limitations, including donor site morbidity, infection, and scarring. Since extensive research on conventional techniques has not provided sufficient long-term results, there has been a shift toward dermal substitutes made from regenerative biomaterials that can aid wound management and support tissue restoration. This structured review will introduce the challenges posed by complex skin defects, the limitations of autologous skin grafts and conventional reconstruction techniques, and the emerging field of dermal substitutes and biomimetic scaffolds. Moreover, the native dermis is presented as a blueprint for biomimetic scaffold design, along with key principles to consider when engineering a dermal scaffold, from architecture and porosity to angiogenic potential. A critical examination of the main classes of available dermal substitutes and their clinical performance is conducted, highlighting their limitations and the translational gaps in current evidence. Although the current pool of biomaterials still faces challenges in accurately mimicking the properties and architecture of natural skin, future perspectives offer promising alternatives that could overcome these limitations. Full article

Background/Objectives: Melanoma remains one of the most aggressive skin cancers worldwide, with rising incidence and persistent therapeutic challenges, particularly in advanced diseases. Drug repositioning has emerged as a cost- and time-efficient strategy for identifying adjunctive treatments, and antihypertensive medications have attracted attention for their potential off-target antitumor and immunomodulatory effects. This scoping review aimed to map and critically appraise the evidence on the repositioning of antihypertensive drugs for melanoma management. Methods: The review followed the JBI methodology, and the results were reported in accordance with the PRISMA-ScR guidelines. Searches were conducted in July 2025 and updated in May 2026 in PubMed, Scopus, and Web of Science. For Methodological Quality and Risk-of-bias assessment, the SYRCLE Risk of Bias tool was employed for animal studies. Results: This review included 37 studies. β-Blockers, particularly propranolol, were the most frequently investigated agents (n = 21). Several studies reported antiproliferative, pro-apoptotic, antiangiogenic, and immunomodulatory effects; however, these findings were not uniform. Absent direct antiproliferative effects, biphasic dose responses, lack of angiogenic effects, and outcomes dependent on drug concentration, treatment schedule, and experimental model were also reported. Agents targeting the renin–angiotensin system and calcium channels similarly produced heterogeneous and context-dependent findings. The animal studies frequently presented high or unclear risk of bias, particularly because of incomplete reporting of randomization, allocation concealment, and blinding. No formal methodological quality assessment was performed for the in vitro studies. Conclusions: Antihypertensive agents, particularly β-blockers, show promising but heterogeneous preclinical signals in melanoma. However, the available evidence is not sufficient to establish reproducible efficacy or translational validity. Standardized and methodologically rigorous preclinical studies are required before these agents can be considered for clinical investigation as adjunctive melanoma therapies. Full article

Cancer therapy is increasingly focused on manipulating the tumor microenvironment rather than directly eradicating malignant cells. Vascular-targeting strategies are emerging, and calcium-mediated vascular disruption is an exciting approach through which rapid and irreversible blood flow shutdown can be achieved. Here, we overview the molecular and physiological basis of calcium signaling in vascular homeostasis and outline how unregulated calcium dysfunctions in endothelial cells compromise their functionality and represent therapeutic opportunities. Elevation of intracellular calcium concentrations in endothelial cells promotes their dysfunction, coagulation, mitochondrial collapse, oxidative stress, and ultimately apoptosis, resulting in catastrophic vascular depletion and secondary necrosis that follows such collapse. A promising area of calcium-mediated attack is the emergence of exciting nanotechnologies that result in the development of calcium phosphate, calcium carbonate, and calcium peroxide nanoparticles, exploiting the enhanced permeability and retention effect of nanoparticle therapeutics to achieve selective tumor accumulation and controlled calcium release. Indeed, hybrid therapeutic platforms that couple calcium dysregulation with chemotherapy, photodynamic therapy, sonodynamic therapy, immunotherapy, or thermal ablation can exhibit pronounced antitumor effects through synergistic means. There is good preclinical evidence for the feasibility of vascular collapse mediated via calcium dysregulation. The transition of calcium to the clinic faces hurdles in relation to biosafety, how to achieve precise delivery, pharmacokinetics, and regulatory harmonization. Compared to traditional vascular disrupting agents and anti-angiogenic therapies, calcium modalities can provide rapid occlusion of vessels, are less prone to resistance development, and potentially have less systemic toxicity. Overall, calcium-mediated vascular collapse is thus an exciting next-generation technology for the vascular-targeted treatment of cancer, and likely to play an important role in precision oncology therapeutics. Full article

Growth factors are molecules that interact with specific membrane receptors and induce cellular proliferation. In malignancy, this growth factor–receptor interaction constitutes one of the “hallmarks of cancer” and may result in uncontrolled cell growth. Proadrenomedullin N-terminal 20 peptide (PAMP) derives from proadrenomedullin and acts as an angiogenic peptide, and recent studies suggest it may be a tumor growth factor. In addition, it has been suggested that CXCR7 may be PAMP’s membrane receptor in particular cell types. Here, we combined advanced docking and molecular dynamic simulation studies to evaluate PAMP’s binding to CXCR7. Then, we used two melanoma cell lines and checked whether PAMP influences their shape, proliferation, migration, and invasion capacities. The signal transduction activated by PAMP was tested by Western blotting, and receptor involvement was investigated with specific inhibitors. This study shows that PAMP binds to active site 1 of CXCR7. It also increases melanoma cell proliferation through an autocrine growth loop. In contrast, PAMP reduced migration and invasion of these cells in a dose-dependent manner. PAMP was also responsible for modifying the actin cytoskeleton of both cell lines, producing a more elongated morphology. In addition, the presence of PAMP elevated ERK and AKT phosphorylation and increased CXCR7 and β-arrestin expression. Furthermore, specific inhibitors confirmed that these effects are mediated by the CXCR7/CXCR4/β-arrestin axis. In summary, we have shown that PAMP acts as a growth factor for melanoma cells while reducing their migration and invasion potential. These effects seem to be mediated by the CXCR7/CXCR4/β-arrestin axis. Altogether, these results suggest that PAMP inhibitors may be used as antitumor agents in melanoma. Full article

Alveolar bone resorption after tooth extraction complicates subsequent dental implant placement. OsteoBiol^® GTO^® (Tecnoss^®, Giaveno, Italy) is an innovative pre-hydrated heterologous collagenated bone mix blended with a thermosensitive copolymer (OsteoBiol^® TSV Gel) that has demonstrated osteoconductive properties. Despite direct contact with blood vessels upon socket filling, its pro-angiogenic potential has not been directly investigated on endothelial cells. Thus, in this study, an in vitro model, consisting of the EA.hy926 endothelial cell line exposed to different OsteoBiol^® GTO^® soaking preparations [original soaking (OS), centrifuged soaking (CS), and diluted soaking (DS)] at multiple concentrations (1, 5, 10, and 20 mg/mL) was established to identify optimal experimental conditions and characterize the underlying molecular mechanisms. Cell viability and collagen release quantification led to the selection of 10 mg/mL OS as the most suitable condition. Under this condition, OsteoBiol^® GTO^® induces an early increase in Cyclooxygenase-2 (COX-2) protein expression and Prostaglandin E-2 (PGE2) secretion, followed by upregulation of Vascular Endothelial Growth Factor (VEGF) protein expression and phosphorylation of Endothelial Nitric Oxide Synthase (eNOS) at serine 1177. The tube formation assay confirmed the pro-angiogenic functional outcome. These results suggest an association between the pro-angiogenic response of endothelial cells to OsteoBiol^® GTO^® and modulation of the COX-2/PGE2/VEGF axis. This effect could be attributed to collagen accumulation in the OS, thereby representing a novel and promising pro-angiogenic mechanism with potential implications for wound healing and guided bone regeneration following tooth extraction. Full article

Background/Objectives: Time-varying low-frequency electromagnetic fields (LF-EMFs), including pulsed electromagnetic fields (PEMFs) and sinusoidal low-frequency electromagnetic fields, have been investigated as modulators of tissue repair and vascular remodeling. Although numerous studies report pro-angiogenic effects in endothelial systems, the underlying mechanisms remain incompletely understood. This review synthesizes evidence for LF-EMF-induced endothelial angiogenesis and evaluates emerging mechanistic explanations. Methods: Literature was identified through searches of PubMed, Web of Science, and Google Scholar through March 2026. Peer-reviewed studies emphasizing in vitro endothelial angiogenesis models were prioritized, with selected in vivo studies included when relevant to mechanistic interpretation. The review was conducted as a narrative synthesis rather than a systematic review or meta-analysis. Results: Experimental evidence indicates that LF-EMF exposure can enhance endothelial proliferation, migration, sprouting, tube formation, and survival across diverse model systems. Reported mechanisms include modulation of growth factor signaling, calcium-dependent pathways, nitric oxide production, cytoskeletal remodeling, and mechanotransduction. Reexamination of early ultrastructural studies suggests that membrane ruffling, vacuole formation, and vesicular structures observed following LF-EMF exposure may be interpreted within the framework of macropinocytosis and vesicular trafficking, providing a potential mechanistic link between electromagnetic stimulation and endothelial morphogenesis. Conclusions: Current evidence supports the conclusion that LF-EMFs can modulate key endothelial processes involved in angiogenesis and vascular remodeling. Membrane trafficking and macropinocytosis provide a biologically plausible framework linking historical observations with contemporary endothelial cell biology, although direct experimental validation is needed. Future progress will require standardized exposure paradigms and mechanistic studies using physiologically relevant angiogenesis models. Full article