Search Results (47)

Background: Chronic obstructive pulmonary disease (COPD) has higher rates among the general population, so early identification and prevention is the goal. The mechanisms of COPD development have not been completely established, although it has been demonstrated that endothelial dysfunction plays an important role. However, to date, the measurement of endothelial dysfunction is still invasive or not fully established. Nailfold video capillaroscopy (NVC) is a safe, non-invasive diagnostic tool that can be used to easily evaluate the microcirculation and can show any possible endothelial dysfunctions early on. The aim of this review is to evaluate if nailfold microcirculation abnormalities can reflect altered pulmonary vasculature and can predict the risk of cardiovascular comorbidities in COPD patients. Methods: A systematic literature search concerning COPD was performed in electronic databases (PUBMED, UpToDate, Google Scholar, ResearchGate), supplemented with manual research. We searched in these databases for articles published until March 2024. The following search words were searched in the databases in all possible combinations: chronic obstructive pulmonary disease (COPD), endothelial damage, vascular impairment, functional evaluation, capillaroscopy, video capillaroscopy, nailfold video capillaroscopy. Only manuscripts written in English were considered for this review. Papers were included only if they were able to define a relationship between COPD and endothelium dysfunction. Results: The search selected 10 articles, and among these, only three previous reviews were available. Retinal vessel imaging, flow-mediated dilation (FMD), and skin autofluorescence (AF) are reported as the most valuable methods for assessing endothelial dysfunction in COPD patients. Conclusions: It has been assumed that decreased nitric oxide (NO) levels leads to microvascular damage in COPD patients. This finding allows us to assume NVC’s potential effectiveness in COPD patients. However, this potential link is based on assumption; further investigations are needed to confirm this hypothesis. Full article

The impact of visual impairment, such as blindness, on quality of life is immeasurable. However, effective ocular drug delivery into the eyes has not yet been established, primarily due to the impermeability imposed by the blood–retinal barrier (BRB) based on the tight junctions and efflux transporters at the endothelium or the epithelium in oral or intravenous administration, as well as the dilution with tear fluid and excretion through the nasolacrimal duct in eye drop administration. Furthermore, intravitreous injections induce pain and fear in patients. Unmet medical needs persist in ocular diseases such as age-related macular degeneration and diabetic retinopathy. Therefore, innovative non-invasive administration methods should be developed. Drug-releasing soft contact lenses (DR-SCLs) affixed to the eye’s surface can continuously and locally deliver their loaded drugs to the eyes. The use of DR-SCLs is expected to greatly enhance the bioavailability and patient adherence to the drug regimen. It is known that several solute carrier (SLC) transporters are expressed in various parts of the eyes, including the cornea, the ciliary body, and the bulbar conjunctiva. Carrier-mediated transport through SLC transporters may occur in addition to passive diffusion. Moreover, nanoparticles can be loaded into DR-SCLs, offering various intelligent approaches based on modifications to induce receptor-mediated endocytosis/transcytosis or to control the loaded drug release within this delivery system. In this perspective review, I discuss the implementation and potential of DR-SCL-mediated ocular drug delivery, particularly focusing on low-molecular-weight compounds because of their fine distribution in living body, ease of handling, and ease of manufacturing. Full article

The outer blood–retina barrier (oBRB), comprises tightly connected retinal pigment epithelium (RPE) cells, Bruch’s membrane, and choroid blood vessels, and is essential for retinal health and normal visual function. Disruption of the RPE barrier and its dysfunction can lead to retinal disorders such as age-related macular degeneration (AMD). In the present study, we investigated the essential role of choroid endothelial cells (ECs) in the RPE barrier formation process and its dysfunction. We discovered that ECs promoted RPE barrier formation through angiocrine signaling. Through blocking or activating endothelial Notch signaling and conducting experiments in vitro and in vivo, we confirmed that endothelial Notch signaling regulated the expression of heparin-binding epidermal growth factor (HBEGF) and consequently impacted the expression and activity of matrix metalloproteinases (MMP)-9 in RPE cells. This modulation influenced the RPE extracellular matrix deposition, tight junctions and RPE barrier function. In in vivo experiments, the intravitreal administration of recombinant HBEGF (r-HBEGF) alleviated the RPE barrier disruption induced by subretinal injection (SI) or laser treatment and also rescued RPE barrier disruption in endothelial Notch-deficient mice. Our results showed that the endothelial Notch signaling drove HBEGF expression through angiocrine signaling and effectively improved RPE barrier function by regulating the MMP-9 expression in RPE cells. It suggests that the modulation of Notch signaling in the choroidal endothelium may offer a novel therapeutic strategy for retinal degenerative diseases. Full article

Previous studies have revealed that norrin can reverse vascular endothelial-growth-factor (VEGF)-induced permeability in a β-catenin-dependent pathway. Here, we have explored the contribution of disheveled-1 (DVL1) in norrin-induced blood-retinal barrier (BRB) restoration. We provide evidence that in addition to canonical signaling, DVL1 promotes tight junction (TJ) stabilization through a novel, non-canonical signaling pathway involving direct claudin-5 (CLDN5) binding. Immunofluorescence staining of rat retinal cross-sections showed enriched expression of DVL1 and 3 at endothelial capillaries and co-localization with CLDN5 and ZO-1 at the TJ complex in primary bovine retinal endothelial cells (BRECs). Barrier properties of BRECs were determined via measurements of trans-endothelial electrical resistance (TEER) or permeability to 70 kDa RITC-dextran. These studies demonstrated that norrin restoration of barrier properties after VEGF treatment required DVL1 as an siRNA knockdown of Dvl1 but not Dvl2 or Dvl3, reduced basal barrier properties and ablated norrin-induced barrier restoration. However, loss of Dvl1 did not decrease β-catenin signaling activity as measured by Axin2 mRNA expression, suggesting the contribution of a non-canonical pathway. DVL and TJ protein interactions were analyzed via co-immunoprecipitation of endogenous protein in BRECs, which demonstrated that DVL1 interacts with both CLDN5 and ZO-1, while DVL3 interacts only with ZO-1. These interactions were most abundant after inducing BRB restoration by treating BRECs with VEGF and norrin. DVL has previously been shown to form intramolecular bindings between the C-terminal PDZ-binding motif (PDZ-BM) with an internal PDZ domain. Co-transfection of HEK293 cells with DVL1 and CLDN5 or relevant mutants revealed that DVL1 interacts with CLDN5 through the DVL PDZ domain binding, CLDN5 PDZ-BM, in competition with DVL1 PDZ-BM, since DVL/CLDN5 interaction increases with deletion of the DVL1 PDZ-BM and decreases by co-expressing the C-terminal fragment of DVL1 containing the PDZ-BM or through deletion of CLDN5 PDZ-BM. In BREC cells, transfection of the C-terminal fragment of DVL1 downregulates the expression of CLDN5 but does not affect the expression of other proteins of the TJs, including ZO-1, occludin, CLDN1 or VE-cadherin. Blocking DVL1/CLDN5 interaction increased basal permeability and prevented norrin induction of barrier properties after VEGF. Combined with previous data, these results demonstrate that norrin signals through both a canonical β-catenin pathway and a non-canonical signaling pathway by which DVL1 directly binds to CLDN5 to promote barrier properties. Full article

Inflammatory, vasculogenic, and profibrogenic factors have been previously reported in vitreous (VH) and aqueous (AH) humors in myopic patients who underwent cataract surgery. In light of this, we selected some mediators for AH and anterior-capsule-bearing lens epithelial cell (AC/LEC) analysis, and AH expression was correlated with LEC activation (epithelial–mesenchymal transition and EMT differentiation) and axial length (AL) elongation. In this study, AH (97; 41M/56F) and AC/LEC samples (78; 35M/43F) were collected from 102 patients who underwent surgery, and biosamples were grouped according to AL elongation. Biomolecular analyses were carried out for AH and LECs, while microscopical analyses were restricted to whole flattened AC/LECs. The results showed increased levels of interleukin (IL)-6, IL-8, and angiopoietin-2 (ANG)-2 and decreased levels of vascular endothelium growth factor (VEGF)-A were detected in AH depending on AL elongation. LECs showed EMT differentiation as confirmed by the expression of smooth muscle actin (α-SMA) and transforming growth factor (TGF)-βR1/TGFβ isoforms. A differential expression of IL-6R/IL-6, IL-8R/IL-8, and VEGF-R1/VEGF was observed in the LECs, and this expression correlated with AL elongation. The higher VEGF-A and lower VEGF-D transcript expressions were detected in highly myopic LECs, while no significant changes were monitored for VEGF-R transcripts. In conclusion, these findings provide a strong link between the AH protein signature and the EMT phenotype. Furthermore, the low VEGF-A/ANG-2 and the high VEGF-A/VEGF-D ratios in myopic AH might suggest a specific inflammatory and profibrogenic pattern in high myopia. The highly myopic AH profile might be a potential candidate for rating anterior chamber inflammation and predicting retinal distress at the time of cataract surgery. Full article

Hyperglycemia is a crucial risk factor for cardiovascular diseases. Chronic inflammation is a central characteristic of obesity, leading to many of its complications. Recent studies have shown that high glucose activates Yes-associated protein 1 (YAP) by suppressing AMPK activity in breast cancer cells. Metformin is a commonly prescribed anti-diabetic drug best known for its AMPK-activating effect. However, the role of YAP in the vasoprotective effect of metformin in diabetic endothelial cell dysfunction is still unknown. The present study aimed to investigate whether YAP activation plays a role in obesity-associated endothelial dysfunction and inflammation and examine whether the vasoprotective effect of metformin is related to YAP inhibition. Reanalysis of the clinical sequencing data revealed YAP signaling, and the YAP target genes CTGF and CYR61 were upregulated in aortic endothelial cells and retinal fibrovascular membranes from diabetic patients. YAP overexpression impaired endothelium-dependent relaxations (EDRs) in isolated mouse aortas and increased the expression of YAP target genes and inflammatory markers in human umbilical vein endothelial cells (HUVECs). High glucose-activated YAP in HUVECs and aortas was accompanied by increased production of oxygen-reactive species. AMPK inhibition was found to induce YAP activation, resulting in increased JNK activity. Metformin activated AMPK and promoted YAP phosphorylation, ultimately improving EDRs and suppressing the JNK activity. Targeting the AMPK–YAP–JNK axis could become a therapeutic strategy for alleviating vascular dysfunction in obesity and diabetes. Full article

Recently, stable gastric pentadecapeptide BPC 157 therapy by activation of collateral pathways counteracted various occlusion/occlusion-like syndromes, vascular, and multiorgan failure, and blood pressure disturbances in rats with permanent major vessel occlusion and similar procedures disabling endothelium function. Thereby, we revealed BPC 157 cytoprotective therapy with strong vascular rescuing capabilities in glaucoma therapy. With these capabilities, BPC 157 therapy can recover glaucomatous rats, normalize intraocular pressure, maintain retinal integrity, recover pupil function, recover retinal ischemia, and corneal injuries (i.e., maintained transparency after complete corneal abrasion, corneal ulceration, and counteracted dry eye after lacrimal gland removal or corneal insensitivity). The most important point is that in glaucomatous rats (three of four episcleral veins cauterized) with high intraocular pressure, all BPC 157 regimens immediately normalized intraocular pressure. BPC 157-treated rats exhibited normal pupil diameter, microscopically well-preserved ganglion cells and optic nerve presentation, normal fundus presentation, nor- mal retinal and choroidal blood vessel presentation, and normal optic nerve presentation. The one episcleral vein rapidly upgraded to accomplish all functions in glaucomatous rats may correspond with occlusion/occlusion-like syndromes of the activated rescuing collateral pathway (azygos vein direct blood flow delivery). Normalized intraocular pressure in glaucomatous rats corresponded to the counteracted intra-cranial (superior sagittal sinus), portal, and caval hypertension, and aortal hypotension in occlusion/occlusion-like syndromes, were all attenuated/eliminated by BPC 157 therapy. Furthermore, given in other eye disturbances (i.e., retinal ischemia), BPC 157 instantly breaks a noxious chain of events, both at an early stage and an already advanced stage. Thus, we further advocate BPC 157 as a therapeutic agent in ocular disease. Full article

The present article discusses the role of light in altering autophagy, both within the outer retina (retinal pigment epithelium, RPE, and the outer segment of photoreceptors) and the inner choroid (Bruch’s membrane, BM, endothelial cells and the pericytes of choriocapillaris, CC). Here autophagy is needed to maintain the high metabolic requirements and to provide the specific physiological activity sub-serving the process of vision. Activation or inhibition of autophagy within RPE strongly depends on light exposure and it is concomitant with activation or inhibition of the outer segment of the photoreceptors. This also recruits CC, which provides blood flow and metabolic substrates. Thus, the inner choroid and outer retina are mutually dependent and their activity is orchestrated by light exposure in order to cope with metabolic demand. This is tuned by the autophagy status, which works as a sort of pivot in the cross-talk within the inner choroid/outer retina neurovascular unit. In degenerative conditions, and mostly during age-related macular degeneration (AMD), autophagy dysfunction occurs in this area to induce cell loss and extracellular aggregates. Therefore, a detailed analysis of the autophagy status encompassing CC, RPE and interposed BM is key to understanding the fine anatomy and altered biochemistry which underlie the onset and progression of AMD. Full article

The clinical success of neutralizing vascular endothelial growth factor (VEGF) has unequivocally identified VEGF as a driver of retinal edema that underlies a variety of blinding conditions. VEGF is not the only input that is received and integrated by the endothelium. For instance, the permeability of blood vessels is also regulated by the large and ubiquitously expressed transforming growth factor beta (TGF-β) family. In this project, we tested the hypothesis that members of the TGF-β family influence the VEGF-mediated control of the endothelial cell barrier. To this end, we compared the effect of bone morphogenetic protein-9 (BMP-9), TGF-β1, and activin A on the VEGF-driven permeability of primary human retinal endothelial cells. While BMP-9 and TGF-β1 had no effect on VEGF-induced permeability, activin A limited the extent to which VEGF relaxed the barrier. This activin A effect was associated with the reduced activation of VEGFR2 and its downstream effectors and an increased expression of vascular endothelial tyrosine phosphatase (VE-PTP). Attenuating the expression or activity of VE-PTP overcame the effect of activin A. Taken together, these observations indicate that the TGF-β superfamily governed VEGF-mediated responsiveness in a ligand-specific manner. Furthermore, activin A suppressed the responsiveness of cells to VEGF, and the underlying mechanism involved the VE-PTP-mediated dephosphorylation of VEGFR2. Full article

Acquired vitelliform lesions (AVLs) are associated with a large spectrum of retinal diseases, among which is age-related macular degeneration (AMD). The purpose of this study was to characterize AVLs’ evolution in AMD patients using optical coherence tomography (OCT) technology and ImageJ software. We measured AVLs’ size and density and followed their impacts over surrounding retinal layers. Average retinal pigment epithelium (RPE) thickness in the central 1 mm quadrant (45.89 ± 27.84 µm vs. 15.57 ± 1.40 µm) was significantly increased, as opposed to the outer nuclear layer (ONL) thickness, which was decreased (77.94 ± 18.30 µm vs. 88.64 ± 7.65 µm) in the vitelliform group compared to the control group. We found a continuous external limiting membrane (ELM) in 55.5% of the eyes compared to a continuous ellipsoid zone (EZ) in 22.2% of the eyes in the vitelliform group. The difference between the mean AVLs’ volume at baseline compared to the last visit for the nine eyes with ophthalmologic follow-up was not statistically significant (p = 0.725). The median follow-up duration was 11 months (range 5–56 months). Seven eyes (43.75%) were treated with intravitreal anti-vascular endothelium growth factor (anti-VEGF) agent injections, in which we noted a 6.43 ± 9 letter decrease in the best-corrected visual acuity (BCVA). The increased RPE thickness could suggest hyperplasia contrary to the decreased ONL, which could mirror the impact of the vitelliform lesion on photoreceptors (PR). Eyes that received anti-VEGF injections did not show signs of improvement regarding BCVA. Full article

The interaction between leukocytes and cytokine-activated retinal endothelium is an initiating step in non-infectious uveitis involving the posterior eye, mediated by cell adhesion molecules. However, because cell adhesion molecules are required for immune surveillance, therapeutic interventions would ideally be employed indirectly. Using 28 primary human retinal endothelial cell isolates, this study sought to identify transcription factor targets for reducing levels of the key retinal endothelial cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, and limiting leukocyte binding to the retinal endothelium. Five candidate transcription factors—C2CD4B, EGR3, FOSB, IRF1, and JUNB—were identified by differential expression analysis of a transcriptome generated from IL-1β- or TNF-α-stimulated human retinal endothelial cells, interpreted in the context of the published literature. Further filtering involved molecular studies: of the five candidates, C2CD4B and IRF1 consistently demonstrated extended induction in IL-1β- or TNF-α-activated retinal endothelial cells and demonstrated a significant decrease in both ICAM-1 transcript and ICAM-1 membrane-bound protein expression by cytokine-activated retinal endothelial cells following treatment with small interfering RNA. RNA interference of C2CD4B or IRF1 significantly reduced leukocyte binding in a majority of human retinal endothelial cell isolates stimulated by IL-1β or TNF-α. Our observations suggest that the transcription factors C2CD4B and IRF1 may be potential drug targets for limiting leukocyte–retinal endothelial cell interactions in non-infectious uveitis involving the posterior eye. Full article

Diabetes mellitus may cause severe damage to retinal blood vessels. The central aim of this study was to test the hypothesis that sulodexide, a mixture of glycosaminoglycans, has a protective effect against hyperglycemia-induced endothelial dysfunction in the retina. Functional studies were performed in isolated porcine retinal arterioles. Vessels were cannulated and incubated with highly concentrated glucose solution (HG, 25 mM D-glucose) +/− sulodexide (50/5/0.5 μg/mL) or normally concentrated glucose solution (NG, 5.5 mM D-glucose) +/− sulodexide for two hours. Endothelium-dependent and endothelium-independent vasodilatation were measured by videomicroscopy. Reactive oxygen species (ROS) were quantified by dihydroethidium (DHE) fluorescence. Using high-pressure liquid chromatography (HPLC), the intrinsic antioxidant properties of sulodexide were investigated. Quantitative PCR was used to determine mRNA expression of regulatory, inflammatory, and redox genes in retinal arterioles, some of which were subsequently quantified at the protein level by immunofluorescence microscopy. Incubation of retinal arterioles with HG caused significant impairment of endothelium-dependent vasodilation, whereas endothelium-independent responses were not affected. In the HG group, ROS formation was markedly increased in the vascular wall. Strikingly, sulodexide had a protective effect against hyperglycemia-induced ROS formation in the vascular wall and had a concentration-dependent protective effect against endothelial dysfunction. Although sulodexide itself had only negligible antioxidant properties, it prevented hyperglycemia-induced overexpression of the pro-oxidant redox enzymes, NOX4 and NOX5. The data of the present study provide evidence that sulodexide has a protective effect against hyperglycemia-induced oxidative stress and endothelial dysfunction in porcine retinal arterioles, possibly by modulation of redox enzyme expression. Full article

Cytochrome P450 (CYP) 1B1 is a heme-containing monooxygenase found mainly in extrahepatic tissues, including the retina. CYP1B1 substrates include exogenous aromatic hydrocarbons, such as dioxins, and endogenous bioactive compounds, including 17β-estradiol (E2) and arachidonic acid. The endogenous compounds and their metabolites are mediators of various cellular and physiological processes, suggesting that CYP1B1 activity is likely important in maintaining proper cellular and tissue functions. We previously demonstrated that lack of CYP1B1 expression and activity are associated with increased levels of reactive oxygen species and oxidative stress in the retinal vasculature and vascular cells, including retinal endothelial cells (ECs). However, the detailed mechanism(s) of how CYP1B1 activity modulates redox homeostasis remained unknown. We hypothesized that CYP1B1 metabolism of E2 affects bone morphogenic protein 6 (BMP6)-hepcidin-mediated iron homeostasis and lipid peroxidation impacting cellular redox state. Here, we demonstrate retinal EC prepared from Cyp1b1-deficient (Cyp1b1^−/−) mice exhibits increased estrogen receptor-α (ERα) activity and expresses higher levels of BMP6. BMP6 is an inducer of the iron-regulatory hormone hepcidin in the endothelium. Increased hepcidin expression in Cyp1b1^−/− retinal EC resulted in decreased levels of the iron exporter protein ferroportin and, as a result, increased intracellular iron accumulation. Removal of excess iron or antagonism of ERα in Cyp1b1^−/− retinal EC was sufficient to mitigate increased lipid peroxidation and reduce oxidative stress. Suppression of lipid peroxidation and antagonism of ERα also restored ischemia-mediated retinal neovascularization in Cyp1b1^−/− mice. Thus, CYP1B1 expression in retinal EC is important in the regulation of intracellular iron levels, with a significant impact on ocular redox homeostasis and oxidative stress through modulation of the ERα/BMP6/hepcidin axis. Full article

Purpose: To investigate iris atrophy in Posner–Schlossman syndrome (PSS). Methods: Sixty-one patients with PSS were included. Using swept-source optical coherence tomography, the thickness of anterior border layer (A), middle stromal layer (M), and the posterior pigmented epithelial layer (P) of iris were measured at 500 μm, 1000 μm, 1500 μm, 2000 μm, and 2500 μm from the pupillary edge in both PSS-affected and fellow eyes. The relationships between iris thickness and corneal endothelium density, cup-to-disc (C/D) ratio, and retinal nerve fiber layer (RNFL) thickness were also estimated in PSS-affected eyes. Results: Iris thickness parameters, including M500, M1000, A1500, A2000, P2000, and P2500, were significantly thinner in PSS-affected eyes than in fellow eyes (all p < 0.05). Moreover, M500 and M1000 were significantly associated with corneal endothelium density (p = 0.047 and 0.018, respectively), and M500 was significantly associated with C/D ratio (p = 0.001) and RNFL thickness (p = 0.037) in PSS-affected eyes. Conclusions: Iris showed significant thinning and atrophy in PSS-affected eyes, and iris stromal thickness close to the pupillary edge could be a novel clinical predictor of the changes in corneal endothelium, C/D ratio, and RNFL thickness in PSS. Full article

Background: Retinal ischemia-reperfusion (I/R) injury often results in intractable visual impairments. The survival of retinal capillary endothelial cells is crucial for the treatment of retinal I/R injury. How to protect retinal endothelia from damage is a challenging work. Withaferin A, a small molecule derived from plants, has antibacterial and anti-inflammatory effects and has been used for about millennia in traditional medicine. The present study aimed to investigate the potential protective effect of withaferin A on retinal I/R injury. Methods: The drug-likeness of withaferin A was evaluated by the SwissADME web tool. The potential protective effect of withaferin A on the I/R-induced injury of human retinal microvascular endothelial cells (HRMECs) was investigated using multiple approaches. RNA sequencing was performed and associated mechanistic signaling pathways were analyzed based on the Kyoto Encyclopedia of Genes and Genomes data. The analytical results of RNA sequencing data were further validated by in vitro and in vivo experiments. Results: Withaferin A reduced the I/R injury-induced apoptotic death of HRMECs in vitro with a good drug-like property. RNA sequencing and experimental validation results indicated that withaferin A increased the production of the crucial antioxidant molecules heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prdx-1) during I/R. In addition, withaferin A activated the Akt signaling pathway and increased the expression of HO-1 and Prdx-1, thereby exerting an antioxidant effect, attenuated the retinal I/R injury, and decreased the apoptosis of HRMECs. The blockade of Akt completely abolished the effects of withaferin A. Conclusions: The study identified for the first time that withaferin A can protect against the I/R-induced apoptosis of human microvascular retinal endothelial cells via increasing the production of the antioxidants Prdx-1 and HO-1. Results suggest that withaferin A is a promising drug candidate for the treatment of retinal I/R injury. Full article