Search Results (628)

Scaffold architecture shapes tissue regeneration through the mechanical, topographical, and biochemical cues it presents to cells, yet geometrically elaborate scaffolds do not reliably produce more organized tissues, while comparatively simple architectures can exert strong organizational effects. We argue that scaffold performance is better understood by distinguishing geometric complexity from effective informational dimensionality: a relational property of the scaffold–cell system, defined as the number of independently manipulated architectural directions that produce distinguishable, above-noise changes in a jointly measured mechanotransductive response. Unlike structural entropy, fractal dimension, or feature-counting metrics, this construct depends on cellular accessibility, cue persistence, and non-redundancy. Mechanotransduction supplies its biological basis, integrating scaffold-derived cues through focal adhesions, cytoskeletal organization, nuclear deformation, and YAP/TAZ signaling, and we distinguish early resolvability from later organizational stabilization. We outline an operational strategy for estimating both from factorial scaffold libraries, common readout panels, and rank-based analysis of the response mapping, illustrated with selected experimental precedents rather than a systematic evidence sample. Positioned relative to biomimetic, mechanobiology-guided, and morphospace approaches, it yields testable predictions on dimensional compression, redundancy, and the resolvability–stability dissociation. Scaffold design is thus reframed from maximizing complexity or native resemblance toward engineering stable, cell-readable dimensions of organization. Full article

Ovarian cancer (OC) remains the most lethal gynecological malignancy, mostly due to its frequent diagnosis at advanced stages, early peritoneal dissemination, ascites formation, and limited sensitivity of currently available approaches for early detection. Extracellular vesicles (EVs), particularly exosomes, mediate intercellular communication through the transfer of proteins, lipids, metabolites, and nucleic acids. In OC, EV-associated protein profiles reflect both tumor-cell-intrinsic programs and the complex interactions between malignant cells and the peritoneal microenvironment. This review summarizes current evidence regarding the involvement of exosomal proteins in OC progression, with particular emphasis on epithelial–mesenchymal transition, mesothelial reprogramming, extracellular matrix remodeling, angiogenesis, immune suppression, peritoneal dissemination, and platinum resistance. Mechanistic studies indicate that exosomal proteins, including CD44, the integrin α5β1/asparaginyl endopeptidase complex, annexin A2, low-density lipoprotein receptor-related protein 1, and programmed death-ligand 1, can directly contribute to metastatic niche formation and tumor progression. In parallel, proteomic studies of plasma-, serum-, ascites-, peritoneal-fluid-, and uterine-lavage-derived EVs have identified candidate liquid-biopsy biomarkers, including MUC1, EpCAM, FOLR1, integrins, complement- and coagulation-related proteins, and proteins associated with treatment resistance. To integrate the biological significance of proteins reported in OC-associated exosomes, we additionally performed protein–protein interaction and functional enrichment analyses. These analyses revealed interconnected protein groups associated with cell adhesion, oxidative stress adaptation, secretory remodeling, lipid metabolism, extracellular matrix organization, and inflammatory signaling. Taken together, the available evidence supports exosomal proteome profiling as a promising approach for investigating OC dissemination and developing minimally invasive diagnostic and prognostic tools. However, standardized EV isolation, quantitative proteomics, functional validation, and independent clinical cohorts remain essential for translation into clinical practice. Full article

Modern biomaterials are increasingly expected to fulfill multiple functions simultaneously. The aim of this study was to develop multifunctional composite microspheres (MSs) based on poly(L-lactic acid) and hydroxyapatite (PLA/HAp), surface-modified with lactoferrin (Lf). The objective was to create a material exhibiting antimicrobial, pro-adhesive, and osteogenic properties for potential applications in modular tissue engineering. Microspheres with diameters ranging from 70 to 150 µm were fabricated using an oil-in-water emulsification method and subsequently coated with lactoferrin. Antimicrobial efficacy was evaluated against S. aureus, P. aeruginosa, and C. albicans by assessing bacterial adhesion, colony formation, and reduction rates. Osteoblast behavior, including adhesion and differentiation, was investigated using the MC3T3 cell line. The morphology of the samples was analyzed via optical and scanning electron microscopy. The results demonstrated that Lf-coated MSs exerted a significant antibacterial effect against S. aureus and P. aeruginosa. Furthermore, the presence of lactoferrin enhanced cell adhesion to the microspheres, as confirmed by the MTT assay after 24 h of incubation. On day 14, osteogenic differentiation was observed in cultures containing Lf-coated MSs, even in the absence of exogenous differentiating factors. Additionally, hematoxylin and eosin (H/E) staining revealed improved self-assembly of the Lf-modified microspheres. The reduction in microbial adhesion, coupled with enhanced osteoblast attachment, suggests a synergistic effect that may increase the success rate of implant integration at an early stage. Full article

Conventional soldered interconnects—necessarily requiring high-temperature processes to melt solder (tin)—are posing reliability challenges to crystalline silicon solar cell modules due to residual stress stemming from the mismatch of the coefficient of thermal expansion of the materials involved. On the other hand, electrically conductive adhesives (ECAs) have been shown to exhibit sufficiently promising improvements in mechanical and electrical properties to be used as silicon solar cell interconnects. However, the current ECA technology is dominated by ECAs with dispersed silver particles, which makes them costly and could cause embrittlement of the ECA at higher concentrations. This study investigates the potential application of a novel ECA, with composite metal particles, made of a nickel and Sn95Ag4Cu1 solder mixture and dispersed in a high-density polyethylene matrix for the solar cell interconnection. The test PV modules show comparable electrical and mechanical performance to that of soldered cell modules, despite the fact that the ECA application is still rather early in its learning curve. The present study suggests that the novel ECA could lead to a promising alternative to the conventional soldering process and the more costly silver-filled ECAs. Full article

Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment. Full article

Cervical cancer (CC) affects women worldwide, and more than 95% of cases are caused by persistent infection with high-risk human papillomavirus (HR-HPV), such as type 16, which promotes the progression of precancerous lesions to cancer. This study aimed to identify differentially expressed proteins (DEPs) in biopsies from patients with HPV16+ low-grade squamous intraepithelial lesions (LSILs) and from patients with HPV16+ squamous cell carcinoma (SCC) compared with those from HPV-negative normal cervical tissue (NCT HPV−) controls. The samples were analyzed by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) using a data-independent acquisition (DIA) approach. Data processing and differential protein expression analysis were performed with the DIA-NN software (Data-Independent Acquisition Neural Networks), followed by bioinformatics analyses, including Venn diagrams, pathway enrichment, functional interactome, The Cancer Genome Atlas (TCGA)-SCC data integration, and Western blot detection. In total, 1607 DEPs associated with cell adhesion and extracellular matrix proteins were identified in LSILs, whereas 1516 DEPs associated with catalytic and transport activities were identified in SCC; the proteins overexpressed in LSILs (332) were enriched in processes such as metabolism, immune response activation, and stress and cell death responses. In contrast, proteins overexpressed in SCC (205) were associated with the cell cycle, DNA damage, drug metabolism, proteasome degradation, methylation, and immune response. Interaction analyses highlighted proteins related to early proteins 1,5,6 and 7 (E1, E5, E6, and E7). In terms of the two DEPs, S100 calcium binding protein A10 (S100A10/p11) and thymidine phosphorylase (TYMP) were detected in patients with LSIL, HSIL, and SCC at the protein level, consistent with their higher transcript levels in public datasets. Given the small, exploratory cohort, these findings are hypothesis-generating, and validation in a larger, balanced, independent cohort is required. In conclusion, this study identified DEPs associated with the progression of premalignant lesions to SCC that may represent candidate biomarkers and therapeutic targets warranting further investigation. Full article

During development, neurexin-2 (NRXN2) is a cell adhesion molecule localized to presynaptic terminals as well as axonal shafts and immature neurites, where it participates in the regulation of neuronal cell morphogenesis. Given its critical role in early neuronal development, NRXN2 is considered a susceptibility gene product for neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). However, the intracellular signaling mechanisms linking NRXN2 deficiency to abnormal neuronal cell morphology remain unclear. Herein, we investigated the molecular basis of excessive cell morphogenesis induced by the knockdown of NRXN2 using the N1E-115 cell line, a model of neuronal morphogenesis characterized by neurite outgrowth. Silencing NRXN2 using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas13 system resulted in a marked enhancement of process elongation. Mechanistically, we found that Girdin (also called GIV or CCDC88A), a non-receptor guanine nucleotide exchange factor for heterotrimeric G proteins, can mediate the excessive process length phenotype. Transfection of either the regulator of G protein signaling (RGS) domain of RGS3, a GTPase-activating protein for G proteins, or the G protein-binding domain of engulfment and cell motility 1 (ELMO1) rescued the excessive process formation. Similar results were obtained in primary cortical neurons. In addition, these interventions normalized downstream Rac1 activity in cells. Together, our findings elucidate Girdin signaling as a mediator of excessive neuronal process formation following NRXN2 knockdown, providing mechanistic insight into how the loss of function of NRXN2 leads to aberrant cell morphogenesis at least at the molecular and cellular levels. These results suggest that signaling through Girdin may contribute to the morphological abnormalities associated with NRXN2-related neurodevelopmental disorders. Full article

Background and Objectives: Inhaled corticosteroids exert broad immunomodulatory effects in patients with chronic airway diseases. However, their direct impact on pulmonary endothelial immune responses and coronavirus-associated receptor expression remains unclear. This study investigated the effects of budesonide on immune responses and the expression of coronavirus entry receptors in human lung microvascular endothelial cells (HMVEC-L). Materials and Methods: HMVEC-L cells were exposed to budesonide (1 ng/mL), a non-cytotoxic concentration selected based on cell viability assays. The mRNA expression of angiotensin-converting enzyme 2 (ACE2), dipeptidyl peptidase-4 (DPP4), aminopeptidase N (AP-N), intercellular adhesion molecule 1 (ICAM-1), interferon beta (IFN-β), RANTES/CCL5, and interleukin-8 (IL-8/CXCL8) was analyzed using quantitative RT-PCR. The surface expression of ACE2, DPP4, AP-N, and ICAM-1 was assessed using flow cytometry. Secreted IL-8 concentration was measured using ELISA. Results: Budesonide significantly reduced AP-N and DPP4 mRNA expression, accompanied by a decrease in the surface expression of both receptors. ACE2 mRNA expression was transiently reduced, whereas ACE2 surface expression was modestly increased by approximately 5% at 72 h. Budesonide also reduced early ICAM-1 mRNA expression but increased its surface expression at the later time point. Budesonide significantly reduced RANTES/CCL5 and IL-8/CXCL8 mRNA expression, with a corresponding decrease in secreted IL-8 concentration, whereas IFN-β mRNA expression showed a non-significant statistical decrease. Conclusions: Budesonide directly modulates pulmonary endothelial immune responses and coronavirus-associated receptor expression. These findings indicate that budesonide modulates the expression of coronavirus-associated receptors and basal antiviral and inflammatory mediators in HMVEC-L cells. Because viral binding, entry, replication, and infection were not assessed, these results should be interpreted as evidence of receptor and immune-mediator modulation rather than as demonstrating altered coronavirus susceptibility. Full article

Background: Peri-implant infections remain a major cause of dental implant failure, largely due to bacterial adhesion and biofilm formation on implant surfaces. This study aimed to investigate how surface topography influences bacterial colonisation and osteoblastic response. Methods: Titanium discs with machined (Ma), sandblasted, large-grit, and acid-etched (SLA), and nanostructured (Nano) surfaces were prepared, sterilised, and seeded with pre-differentiated dental follicle mesenchymal stem cells. Co-cultures with Enterococcus faecalis (E. faecalis) and Streptococcus oralis (S. oralis) were established under CO₂-free conditions, and cell–bacteria interactions were evaluated using fluorescence microscopy and quantitative image analysis. Results: Nano surfaces showed the highest osteoblastic adhesion and viability, while significantly reducing bacterial proliferation and biofilm formation compared with Ma and SLA surfaces. The sequence of colonisation influenced cell–bacteria dynamics, with early cell attachment limiting subsequent bacterial adhesion. Conclusions: Nano titanium surfaces may offer a dual benefit by promoting osseointegration while limiting bacterial adhesion. These findings support their potential use as surface modifications to reduce peri-implant infection risk and improve long-term implant success. Full article

The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1^S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1^S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1^S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1^WT confers robust neuroprotection. HSPB1^S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1^WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1^S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1^S135F dysregulates stage-specific transglutaminase (TGase) expression—insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy. Full article

Background/Objectives: To summarize evidence on whether anodization of titanium implant abutments modifies abutment surface/physical properties, peri-implant soft tissue esthetics, and biological outcomes compared with machined titanium and alternative abutment materials. Methods: This focused narrative review used a structured, reproducible literature search with dual-reviewer screening and data extraction. The study selection pathway was summarized using a PRISMA-style flow diagram for transparency. Searches of PubMed/MEDLINE, EMBASE, CENTRAL, and Google Scholar were performed, supplemented by gray literature screening and manual searching. Laboratory, animal, and human clinical studies evaluating anodized titanium abutments were eligible. Data were synthesized qualitatively across prespecified domains (surface or physical properties, esthetic outcomes, and biological outcomes). Because the work was designed as a narrative review, protocol registration and formal risk of bias appraisal were not undertaken. Results: Thirty-five studies were included (twenty-five in vitro, three animal, and seven human clinical). Anodization modified oxide layer characteristics and surface chemistry, and was commonly associated with increased hydrophilicity. Esthetically, pink or yellow anodized titanium generally reduced discoloration compared with uncolored titanium, particularly when soft tissue and restorative material thickness were sufficient, whereas zirconia most consistently produced the most favorable color outcomes. In vitro studies frequently reported improved early soft tissue cell responses and, in selected protocols, reduced bacterial adhesion. Reported clinical differences in inflammation indices and peri-implant marginal bone changes were small or inconsistent. Conclusions: Anodization can improve the optical masking of titanium and alter surface wettability and chemistry, but evidence for sustained clinical biological benefit remains limited. Current evidence supports anodization primarily as an esthetic adjunct, while long-term peri-implant biological outcomes appear to be driven by multiple clinical factors beyond surface modification. Full article

The etiology of inflammatory bowel disease (IBD) is not precisely defined. However, it involves environmental factors, genetic predisposition, the involvement of gut microbiota, and abnormal immune response. Angiogenesis seems to be an integral part of IBD. Impairment of the intestinal barrier may represent an initiating or early feature of the disease. Disruption of the epithelial barrier leads to the translocation of microbiota and other antigens into the mucosa, resulting in an enhanced immune response, whereas damage to the vascular barrier is related to endothelial activation and pathologic angiogenesis, both of which promote inflammation. Angiogenesis during IBD is a very complex phenomenon that includes endothelial and immune cells, growth factors, cytokines, adhesion molecules, intestinal microbiota, and signal transduction. It seems that intestinal microvascular hemostasis shifts toward a prothrombotic state, and microthrombi formation exacerbates ischemia. The angiogenic process in IBD is regulated, at least in part, by the intestinal microbiota. Antiangiogenic therapy represents a novel and significant approach to the treatment of IBD. Biologic anti-inflammatory therapy for IBD simultaneously attenuates angiogenesis to a similar degree. However, the expression of VEGF and other growth factors may have dual and opposing effects, probably depending on the stage of the disease. Thus, anti-angiogenic treatment in patients with IBD remains controversial, and clinical trials of anti-angiogenic agents are warranted. Full article

The Zona Pellucida (ZP) and its structural analogs are evolutionarily ancient extracellular matrix components. These are essential for oocyte protection, species-specific gamete recognition, and prevention of polyspermy across Metazoa. Defined by the conserved ZP-domain—comprising ZP-N and ZP-C subdomains—these glycoproteins self-assemble into fibrillar matrices through tightly regulated polymerization. Mechanisms of the regulated polymerization involve furin cleavage, disulfide bonding, and hydrophobic interactions. Once considered a vertebrate innovation, the canonical ZP-domain—defined by its bipartite ZP-N/ZP-C architecture, eight conserved cysteine residues, and capacity for matrix polymerization—is now recognized as an ancient metazoan extracellular module, with homologs identified in basal lineages including Porifera, Cnidaria, and Placozoa. While ZP-like sequences have been reported in choanoflagellates such as Salpingoeca rosetta, these lack the complete canonical features and are considered distant structural relatives rather than true ZP-modules. There they function in cell adhesion and tissue integrity, suggesting an origin predating the evolution of specialized reproductive coats. Previous phylogenetic analyses across 97 metazoan species have revealed that vertebrate ZP genes arose from ancestral duplications of the canonical ZP-module. Accordingly, they give rise to eight subfamilies (ZP1–ZP4, ZPD, ZPAX, ZPX, ZPY), with lineage-specific expansions, losses, and pseudogenization reflecting adaptations to diverse reproductive strategies. Positive selection in sperm-binding regions of ZP2 and ZP3 drives a rapid adaptive evolution. It underscores coevolutionary arms races with sperm ligands, contributing to reproductive isolation and speciation. In invertebrates such as abalone and insects, ZP-domain proteins mediate analogous functions through lineage-specific elaborations, including tandem repeats and domain shuffling. Post-translational modifications, particularly glycosylation, fine-tune sperm receptor specificity and matrix stability. The functional transition from a general protective barrier in early metazoans to a sophisticated gamete recognition interface in vertebrates exemplifies modular evolution. This synthesis highlights the domain-level deep homology of ZP-domain proteins as a foundational element of metazoan extracellular matrices, repurposed through gene duplication, neofunctionalization, and selection to meet the demands of evolving reproductive modes. These insights bridge evolutionary biology, reproductive medicine, and developmental genetics. However, major gaps remain, including unresolved orthology between vertebrate and invertebrate ZP genes, the relative contribution of glycans versus protein backbone in sperm recognition, and the lack of functional evidence for canonical ZP-domain proteins in insects. Future studies integrating glycoproteomics, single-cell transcriptomics, and CRISPR-based models are needed to resolve these questions. Full article

Graphene oxide (GO)-based nanostructured biomaterials have emerged as promising platforms for tissue engineering due to their novel biointeractive properties. In this study, we developed polyamide 6 (PA6) scaffolds by electrospinning using the Nanospider technique. Unlike conventional laboratory-scale electrospinning systems, Nanospider™ employs a wire-based electrode coated with a thin layer of polymer solution, from which nanofibers are continuously generated under a high-voltage electric field, enabling the large-scale fabrication of scaffolds. The scaffolds were then nanostructured with GO to investigate the effect of surface modification on their physicochemical properties, and biological responses. Surface characterization demonstrated that GO incorporation altered the microtexture of PA6 scaffolds, leading to changes in topographical parameters and surface morphology. In vitro studies performed using human stromal HS-5 cells confirmed high cytocompatibility of both GO nanofilms and PA6-GO composites, with preserved metabolic activity and enhanced cell adhesion. Scanning electron microscopy revealed improved spreading, elongated morphology, and increased filopodia formation on GO-modified scaffolds. Gene expression analyses indicated modulation of mechanotransduction- and adhesion-related pathways, including differential regulation of FN1, FAK, and integrin-associated genes, suggesting that GO nanostructuring influences early cell–material interactions through combined effects on surface architecture and chemistry. Ex vivo studies using embryonic tissues derived from chicken embryo Gallus gallus demonstrated effective colonization of connective, cartilage, and bone tissues on GO-modified scaffolds. Collectively, these findings demonstrate that GO nanostructuring of electrospun PA6 scaffolds improves biointerface formation, supports mechanobiological adaptation, and promotes tissue development, highlighting the potential for regenerative medicine. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article