Branch retinal artery occlusion in a 49-year-Old woman taking phentermine.

Purpose: This report describes the presentation of a 49-year-old woman with a branch retinal artery occlusion of the right eye in the setting of taking phentermine, a commonly used weight loss medication. Observations: A 49-year-old woman presented with acute painless vision loss in her right eye and was found to have a branch retinal artery occlusion after taking prescribed dosages of phentermine for weight loss therapy. Fundus examination revealed retinal whitening in the distribution of the superior temporal branch retinal artery, and spectral domain optical coherence tomography demonstrated macular edema. Systemic evaluation was negative for cardiovascular, infectious, or autoimmune etiologies. Based on the retinal findings, the patient was diagnosed with phentermine associated branch retinal artery occlusion. She was followed for nine years with no further complications and her vision remained stable in the right eye. Conclusions and Importance: This case highlights that phentermine, a commonly used weight loss medication, could be associated with ischemic retinopathies. Thus, clinicians should be aware that retinal vascular occlusions may not only occur in those who use recreational amphetamines but also in patients taking the prescribed dosages of a weight loss medication like phentermine.

Formyl Peptide Receptor 1 Inhibits Reparative Angiogenesis and Aggravates Neuroretinal Dysfunction in Ischemic Retinopathy.

PURPOSE: Ischemic retinopathy is the major cause of vision-threatening conditions. Inflammation plays an important role in the pathogenesis of ischemic retinopathy. Formyl peptide receptor 1 (FPR1) has been reported to be implicated in the regulation of inflammatory disorders. However, the role of FPR1 in the progression of ischemic retinal injury has not been fully explained. METHODS: The activation of FPR1 was measured by real-time PCR and western blotting in the retina of OIR. The effect of FPR1 on the expression of inflammatory cytokines and relevant pro-angiogenic factors was assessed between wild-type and FPR1-deficiency OIR mice. The impact of FPR1 on retinal angiogenesis was evaluated through quantifying retinal vaso-obliteration and neovascularization between FPR1+/+ and FPR1-/- OIR mice. At last, the neuronal effect of FPR1 on the ischemic retina was investigated by ERG between wild-type and FPR1-deficient OIR mice. RESULTS: The expression of FPR1 significantly increased in the retina of OIR. Furthermore, FPR1 deficiency downregulated pro-inflammatory and pro-angiogenic factors. Ablation of FPR1 suppressed the retinal pathological neovascularization and promoted reparative revascularization, ultimately improving retinal neural function after ischemic injury. CONCLUSION: In ischemic retinopathy, FPR1 aggravates inflammation and inhibits reparative angiogenesis to exacerbate neuronal dysfunction.

Bilateral sequential ischemic retinopathy and optic neuropathy in IgG1 heavy chain deposition disease.

PURPOSE: To report a case of progressive ischemic retinopathy and optic neuropathy in a patient with heavy chain deposition disease (HCDD), a rare form of monoclonal immunoglobulin deposition disease (MIDD). OBSERVATIONS: Our case describes a 74-year-old woman diagnosed with IgG1 lambda HCDD. After treatment with daratumumab and intravenous IVIG therapy, the patient developed worsening ischemic retinopathy and optic neuropathy, neovascular glaucoma, and bilateral sequential vitreous hemorrhages, necessitating surgical intervention. We present multimodal imaging from the onset of ischemic retinopathy to end-stage maculopathy illustrated by optical coherence tomography (OCT) angiography. Despite discontinuing treatment with daratumumab and providing maximal ocular interventions to control the complications of neovascular disease, the patient's condition progressed, resulting in profound vision loss. CONCLUSIONS AND IMPORTANCE: Our case illustrates the potential for HCDD to cause end-organ disease, including ischemic retinopathy and optic neuropathy, possibly worsened by the patient's underlying cardiovascular risk factor status and medications. Daratumumab, a humanized IgG1 kappa monoclonal antibody that binds to CD38 used to treat specific blood cancers, has been reported to cause disturbances in retinal blood flow, including retinal artery and vein occlusions. It remains to be determined whether careful patient selection or dose adjustments and timing of HCDD treatments could protect vision by reducing the risk of these rare yet severe ocular complications.

Spermine oxidase inhibitor, MDL 72527, reduced neovascularization, vascular permeability, and acrolein-conjugated proteins in a mouse model of ischemic retinopathy.

Disruptions in polyamine metabolism have been identified as contributing factors to various central nervous system disorders. Our laboratory has previously highlighted the crucial role of polyamine oxidation in retinal disease models, specifically noting elevated levels of spermine oxidase (SMOX) in inner retinal neurons. Our prior research demonstrated that inhibiting SMOX with MDL 72527 protected against vascular injury and microglial activation induced by hyperoxia in the retina. However, the effects of SMOX inhibition on retinal neovascularization and vascular permeability, along with the underlying molecular mechanisms of vascular protection, remain incompletely understood. In this study, we utilized the oxygen-induced retinopathy (OIR) model to explore the impact of SMOX inhibition on retinal neovascularization, vascular permeability, and the molecular mechanisms underlying MDL 72527-mediated vasoprotection in the OIR retina. Our findings indicate that inhibiting SMOX with MDL 72527 mitigated vaso-obliteration and neovascularization in the OIR retina. Additionally, it reduced OIR-induced vascular permeability and Claudin-5 expression, suppressed acrolein-conjugated protein levels, and downregulated P38/ERK1/2/STAT3 signaling. Furthermore, our results revealed that treatment with BSA-Acrolein conjugates significantly decreased the viability of human retinal endothelial cells (HRECs) and activated P38 signaling. These observations contribute valuable insights into the potential therapeutic benefits of SMOX inhibition by MDL 72527 in ischemic retinopathy.

Apoptotic Vesicles Modulate Endothelial Metabolism and Ameliorate Ischemic Retinopathy via PD1/PDL1 Axis.

Pathological angiogenesis with subsequent disturbed microvascular remodeling is a major cause of irreversible blindness in a number of ischemic retinal diseases. The current anti-vascular endothelial growth factor therapy can effectively inhibit angiogenesis, but it also brings significant side effects. The emergence of stem cell derived extracellular vesicles provides a new underlining strategy for ischemic retinopathy. Apoptotic vesicles (apoVs) are extracted from stem cells from human exfoliated deciduous teeth (SHED). SHED-apoVs are delivered into the eyeballs of oxygen-induced retinopathy (a most common model of angiogenic retinal dieseases) mice through intravitreal injection. The retinal neovascularization and nonperfusion area, vascular structure, and density changes are observed during the neovascularization phase (P17) and vascular remodeling phase (P21), and visual function is measured. The expression of extracellular acidification rate and lactic acid testing are used to detect endothelial cells (ECs) glycolytic activity. Furthermore, lentivirus and neutralizing antibody are used to block PD1-PDL1 axis, investigating the effects of SHED-apoVs on glycolysis and angiogenic activities. This work shows that SHED-apoVs are taken up by ECs and modulate the ECs glycolysis, leading to the decrease of abnormal neovessels and vascular remodeling. Furthermore, it is found that, at the molecular level, apoVs-carried PD1 interacts with PDL1 on hypoxic ECs to regulate the angiogenic activation. SHED-apoVs inhibit pathological angiogenesis and promote vascular remodeling in ischemic retinopathy partially by modulating ECs glycolysis through PD1/PDL1 axis. This study provides a new potential strategy for the clinical treatment of pathological retinal neovascularization.

Bilateral central retinal vein occlusion following COVID-19 vaccination: Cause or coincidence?

AIM: To report a case of sequential bilateral ischemic central retinal vein occlusion (CRVO) following the third dose of anti-COVID 19 vaccination. METHODS: Observational case report. RESULTS: A 73-year-old Caucasian male patient, with no known medical history, complained of sudden vision loss in his right eye (RE) 18 days following the third dose of Pfizer-BioNTech anti-COVID 19 vaccination. Ten days later, he suffered from sudden vision loss in his left eye (LE).Best-corrected visual acuity was limited to counting fingers at 50cm in both eyes.Fundus examination of both eyes revealed signs of ischemic central retinal vein occlusion (CRVO) with diffuse superficial and deep retinal hemorrhages in all four quadrants. Diagnosis was confirmed of fluorescein angiography.Optical coherent tomography (OCT) showed an ischemic hyperreflectivity and disorganization of the inner retinal layers in both eyes with significantly increased central macular thickness, associated to intraretinal fluid accumulation in LE.An urgent systemic assessment was requested. A mild hypertension was discovered and the rest of the work up was unremarkable. CONCLUSION: To our knowledge, we report the first case of bilateral CRVO in a healthy patient after anti-COVID 19 vaccination. CRVO occurred few days following third shot of vaccine followed by a sequential CRVO in the fellow eye in a patient with recently diagnosed very mild hypertension and no thrombo-embolic risk factors, strongly suggesting a relationship between both events. Nowadays, CRVO should be kept in mind as a potential side effect of Covid-19 vaccination and should be added to the spectrum of their ophthalmic complications.

Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy.

Activation of hypoxia-inducible factor 1α (HIF1α) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1α degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy.

[Optical coherence tomography angiography in diagnosis of changes in macular capillary blood flow in chronic ischemic retinopathy]. / Opticheskaya kogerentnaya tomografiya-angiografiya v diagnostike izmenenii kapillyarnogo krovotoka makuly pri khronicheskoi ishemicheskoi retinopatii.

PURPOSE: Assessment of the indices of macular capillary blood flow and subfoveal choroidal thickness (SCT) using optical coherence tomography angiography in patients with retinal manifestations of ocular ischemic syndrome (RMOIS) associated with atherosclerotic internal carotid artery stenosis. MATERIAL AND METHODS: The study included 34 patients (68 eyes): 21 men, 13 women with RMOIS in one eye. All patients were divided into 2 groups depending on the severity of atherosclerotic internal carotid artery stenosis and ophthalmoscopic picture of the fundus. To obtain objective information we analyzed the degree of decrease in the main indices characterizing macular microcirculation and SCT depending on the severity of RMOIS. RESULTS AND DISCUSSION: Analysis of the results showed relationship between the severity of RMOIS and the deficit in macular microcirculation. The macula of the patients with mild RMOIS was characterized by a decrease in the density of superficial vascular plexus (SVP) and the density of deep capillary plexus (DCP) by 13.5% and 10.5% compared to the controls, respectively; in moderate RMOIS - by 19.7% and 14.6%; in severe RMOIS - by 35.9% and 28%, respectively. With an increase in the severity of RMOIS, the area of the foveal avascular zone increased too: in mild degree RMOIS - by 19%, in moderate - by 38.6%, in severe - by 51%. In proportion to the severity of RMOIS, SCT was reduced: in mild degree RMOIS - by only 8%, in moderate - by 22%, and in severe - by 29.8% of the control. CONCLUSION: The conducted research indicates that pathological changes in RMOIS extend to the entire capillary network of the macula and SCT. With increase in the degree of RMOIS, ischemic changes in all capillary layers of the central parts of the retina proportionally increase in comparison with the control group by 1.15 times in mild degree, by 1.24 times in moderate degree, and by 1.5 times in severe RMOIS.

Lost in Translation: Neurotrophins Biology and Function in the Neurovascular Unit.

The neurovascular unit (NVU) refers to the functional building unit of the brain and the retina, where neurons, glia, and microvasculature orchestrate to meet the demand of the retina's and brain's function. Neurotrophins (NTs) are structural families of secreted proteins and are known for exerting neurotrophic effects on neuronal differentiation, survival, neurite outgrowth, synaptic formation, and plasticity. NTs include several molecules, such as nerve growth factor, brain-derived neurotrophic factor, NT-3, NT-4, and their precursors. Furthermore, NTs are involved in signaling pathways such as inflammation, apoptosis, and angiogenesis in a nonneuronal cell type. Interestingly, NTs and the precursors can bind and activate the p75 neurotrophin receptor (p75NTR) at low and high affinity. Mature NTs bind their cognate tropomyosin/tyrosine-regulated kinase receptors, crucial for maintenance and neuronal development in the brain and retina axis. Activation of p75NTR results in neuronal apoptosis and cell death, while tropomysin receptor kinase upregulation contributes to differentiation and cell growth. Recent findings indicate that modulation of NTs and their receptors contribute to neurovascular dysfunction in the NVU. Several chronic metabolic and acute ischemic diseases affect the NVU, including diabetic and ischemic retinopathy for the retina, as well as stroke, acute encephalitis, and traumatic brain injury for the brain. This work aims to review the current evidence through published literature studying the impact of NTs and their receptors, including the p75NTR receptor, on the injured and healthy brain-retina axis.

Cytochrome P450 1B1: A Key Regulator of Ocular Iron Homeostasis and Oxidative Stress.

Cytochrome P450 (CYP) 1B1 belongs to the superfamily of heme-containing monooxygenases. Unlike other CYP enzymes, which are highly expressed in the liver, CYP1B1 is predominantly found in extrahepatic tissues, such as the brain, and ocular tissues including retina and trabecular meshwork. CYP1B1 metabolizes exogenous chemicals such as polycyclic aromatic hydrocarbons. CYP1B1 also metabolizes endogenous bioactive compounds including estradiol and arachidonic acid. These metabolites impact various cellular and physiological processes during development and pathological processes. We previously showed that CYP1B1 deficiency mitigates ischemia-mediated retinal neovascularization and drives the trabecular meshwork dysgenesis through increased levels of oxidative stress. However, the underlying mechanisms responsible for CYP1B1-deficiency-mediated increased oxidative stress remain largely unresolved. Iron is an essential element and utilized as a cofactor in a variety of enzymes. However, excess iron promotes the production of hydroxyl radicals, lipid peroxidation, increased oxidative stress, and cell damage. The retinal endothelium is recognized as a major component of the blood-retinal barrier, which controls ocular iron levels through the modulation of proteins involved in iron regulation present in retinal endothelial cells, as well as other ocular cell types including trabecular meshwork cells. We previously showed increased levels of reactive oxygen species and lipid peroxidation in the absence of CYP1B1, and in the retinal vasculature and trabecular meshwork, which was reversed by administration of antioxidant N-acetylcysteine. Here, we review the important role CYP1B1 expression and activity play in maintaining retinal redox homeostasis through the modulation of iron levels by retinal endothelial cells. The relationship between CYP1B1 expression and activity and iron levels has not been previously delineated. We review the potential significance of CYP1B1 expression, estrogen metabolism, and hepcidin-ferroportin regulatory axis in the local regulation of ocular iron levels.

Distinguished Functions of Microglia in the Two Stages of Oxygen-Induced Retinopathy: A Novel Target in the Treatment of Ischemic Retinopathy.

Microglia is the resident immune cell in the retina, playing the role of immune surveillance in a traditional concept. With the heated focus on the mechanisms of microglia in pathological conditions, more and more functions of microglia have been discovered. Although the regulating role of microglia has been explored in ischemic retinopathy, little is known about its mechanisms in the different stages of the pathological process. Here, we removed microglia in the oxygen-induced retinopathy model by PLX5622 and revealed that the removal of activated microglia reduced pathological angiogenesis in the early stage after ischemic insult and alleviated the over-apoptosis of photoreceptors in the vessel remodeling phase. Our results indicated that microglia might play distinguished functions in the angiogenic and remodeling stages, and that the inhibition of microglia might be a promising target in the future treatment of ischemic retinopathy.

Polycythemia-Related Proliferative Ischemic Retinopathy Managed with Smoking Cessation: A Case Report.

Ischemic retinopathy characterized by neovascularization could result from several diseases such as proliferative diabetic retinopathy, hypertensive retinopathy, and retinal vein occlusion. However, ocular ischemic conditions caused by polycythemia have rarely been described. We report the first case of polycythemia-related proliferative ischemic retinopathy in a 41-year-old male heavy smoker who had ocular ischemic condition due to secondary polycythemia. He had sudden loss of vision in his right eye vision with vitreous hemorrhage and a tortuous retinal artery. Tracing back to his history, he was a heavy smoker with more than one pack of cigarettes per day for more than 30 years. Laboratory data revealed elevated levels of hemoglobin (17.7 g/dL) and hematocrit (51.6%) without other abnormal findings. We performed retinal photocoagulation on the neovascular areas and the fibrous membrane. Additionally, the patient was advised to quit smoking. Owing to adherence to this treatment, the patient's vision gradually recovered. Although rare, polycythemia can cause retinal ischemic events and should be considered as a sight-threatening disease. Photocoagulation is effective on the regression of the neovascular lesion. Most importantly, changes in lifestyle together with smoking cessation are effective in managing secondary polycythemia. In conclusion, prevention and cessation of tobacco consumption helps improve vision health.

Deletion of Tgfß signal in activated microglia prolongs hypoxia-induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis.

Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia-specific Transforming Growth Factor-ß (Tgfß) receptor knock out mouse model and human iPSC-derived microglia to examine the role of Tgfß signaling in activated microglia during retinal NV. Using a tamoxifen-inducible, microglia-specific Tgfß receptor type 2 (Tgfßr2) knockout mouse [Tgfßr2 KO (ΔMG)] we show that Tgfß signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfß signaling represses expression of the pro-angiogenic factor, Insulin-like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen-induced retinopathy (OIR) we show that Tgfß signaling in activated microglia plays a role in hypoxia-induced NV where a loss in Tgfß signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC-derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor-ß1 (Tgfß1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfß signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfß signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression.

Combination of pigment epithelium derived factor with anti-vascular endothelial growth factor therapy protects the neuroretina from ischemic damage.

Ocular ischemia is a vision-threatening disease, and is a medical condition associated with many ocular diseases. Anti-VEGF therapy has limitations related to its side effects and suppression of physiological revascularization. Pigment epithelium derived factor (PEDF) has anti-angiogenesis and neurotrophic neuroprotective functions and is a promising agent in the treatment of ischemia-induced retinal neurodegeneration. The purpose of this study is to investigate the effect of PEDF and anti-VEGF and the combined therapy on the ischemic rat eye model ex vivo. In this study, the PEDF protein, anti-VEGF drug (Avastin) or the combination of PEDF and Avastin were intravitreally injected immediately after eye enucleation. Then the eyes were incubated in Dulbecco's modified eagle medium (DMEM) at 4 â„ƒ for 14 h. After that the eyes were fixed immediately by formalin. VEGF, PEDF and glial fibrillary acidic protein (GFAP) were detected by immunohistochemical (IHC) staining. The IHC staining intensity was evaluated for each eye. Compared to the groups treated by vehicle, PEDF, and anti-VEGF alone, the value of staining intensity of VEGF and GFAP was significantly reduced in the retina and choroidal vessels of the PEDF/Anti-VEGF treatment group. The intravitreally injected PEDF protein can locate in the retina and the choroidal vessels. Compared to the vehicle-treatment group, both the PEDF-treatment and the PEDF/Anti-VEGF treatment groups showed significantly decreased number of TUNEL-positive nuclei, and the PEDF/Anti-VEGF treatment group had the least TUNEL-positive nuclei. Combination of PEDF and an anti-VEGF drug (Avastin) is a possible therapeutic strategy against ischemic retinal and choroidal diseases.

Generation of Pericytic-Vascular Progenitors from Tankyrase/PARP-Inhibitor-Regulated Naïve (TIRN) Human Pluripotent Stem Cells.

Tankyrase/PARP inhibitor-regulated naïve human pluripotent stem cells (TIRN-hPSC) represent a new class of human stem cells for regenerative medicine that can differentiate into multi-lineage progenitors with improved in vivo functionality. Chemical reversion of conventional, primed hPSC to a TIRN-hPSC state alleviates dysfunctional epigenetic donor cell memory, lineage-primed gene expression, and potentially disease-associated aberrations in their differentiated progeny. Here, we provide methods for the reversion of normal or diseased patient-specific primed hPSC to TIRN-hPSC and describe their subsequent differentiation into embryonic-like pericytic-endothelial "naïve" vascular progenitors (N-VP). N-VP possess improved vascular functionality, high epigenetic plasticity, maintain greater genomic stability, and are more efficient in migrating to and re-vascularizing ischemic tissues than those generated from primed isogenic hPSC. We also describe detailed methods for the ocular transplantation and quantitation of vascular engraftment of N-VP into the ischemia-damaged neural retina of a humanized mouse model of ischemic retinopathy. The application of TIRN-hPSC-derived N-VP will advance vascular cell therapies of ischemic retinopathy, myocardial infarction, and cerebral vascular stroke.

Effect of anti-VEGF treatment on nonperfusion areas in ischemic retinopathy.

In recent years, retinal ischemia such as that which occurs in diabetic retinopathy (DR) and retinal vein occlusion (RVO) has become a hotspot of ischemic retinopathy research. High levels of vascular endothelial growth factor (VEGF) are recognized as a major cause of macular edema (ME) in DR and RVO. High concentrations of VEGF in the vitreous can lead to serious retinal ischemia and hypoxia and form retinal nonperfusion areas (NPAs). Different levels of retinal ischemia can represent disease severity and progression. Anti-VEGF therapy as the first-line treatment for ME has been found to be effective in improving vision, but there are still disputes about whether anti-VEGF therapy could improve retinal ischemia and achieve reperfusion of previously developed retinal NPAs. Here, we review and summarize studies of the effects of anti-VEGF drugs on retinal ischemia, especially NPAs.

Autophagy is required for the promoting effect of angiogenic factor with G patch domain and forkhead-associated domain 1 (AGGF1) in retinal angiogenesis.

OBJECTIVE: To investigate the effect of angiogenic factor with G patch domain and forkhead-associated domain 1 (AGGF1) on retinal angiogenesis in ischemic retinopathy and its association with autophagy. METHODS: RF/6A cells were divided into the control group, hypoxia group and high-glucose group, and the expression of AGGF1 in cells was detected. C57BL/6 J mice were divided into the control group, oxygen-induced retinopathy (OIR) group and diabetic retinopathy (DR) group, and AGGF1 expression in the retina was observed. RF/6A cells were then divided into the control group and different AGGF1 concentration groups, and the expression of autophagy marker, LC3 was detected. Then, RF/6A cells were divided into the control group, AGGF1 group, 3-methyladenine (3-MA, an early autophagy inhibitor) + AGGF1 group and chloroquine (CQ, a late autophagy inhibitor) + AGGF1 group, and the expression of autophagy markers, LC3 and p62, autophagic flux, as well as was key signaling pathway proteins in autophagy, PI3K, AKT, and mTOR was detected. Finally, the cell proliferation, migration and tube formation were detected in the four groups. RESULTS: AGGF1 expression in RF/6A cells and in the retinas of OIR and DR mouse model was found to be increased in the state of hypoxic and high glucose condition. AGGF1 treatment led to increased expressions of LC3 and decreased p62; therby induced autophagic flux, and the phosphorylation of PI3K, AKT and mTOR was down-regulated in RF/6A cells. When autophagy was inhibited by 3-MA or CQ, confirmed by corresponding changes of these indicators of autophagy, cellular proliferation, migration and tube formation of RF/6A cells were weakened by AGGF1 treatment when compared with that of AGGF1 treatment alone. CONCLUSION: This study experimentally revealed that AGGF1 activates autophagy to promote angiogenesis for ischemic retinopathy and inhibition of PI3K/AKT/mTOR pathway may be involved in the activation of autophagy by AGGF1.

Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy.

BACKGROUND: Neovascularization is a leading cause of visual loss typically associated with diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Interleukin-17A (IL-17A) and endoplasmic reticulum (ER) stress both have been demonstrated to play a proangiogenic role in ischemic retinopathies. However, the relationship between IL-17A and ER stress in retinal neovascularization (RNV) under hypoxic conditions and its underlying mechanisms remain unclear. METHODS: In this study, oxygen-induced retinopathy (OIR) mice model was established and intravitreal injections were conducted. Changes of IL-17A and ER stress markers in retinas and cultured primary bone marrow derived macrophage (BMDM) under normoxic or hypoxic conditions were detected. Western blotting, Real-Time RT-PCR, Immunofluorescence assays were conducted to explore the roles and relationship of IL-17A and ER stress in RNV, as well as its underlying mechanisms. RESULTS: Compared to that in normal controls, IL-17A and ER stress markers were all remarkably increased under hypoxic conditions both in vivo and in vitro. Neutralization or knock out of IL-17A decreased ER stress. ER stress inhibitor 4-phenylbutyrate (4-PBA), attenuated the production of IL-17A, suggesting a positive feedback loop between IL-17A and ER stress. Inhibition of IL-17A or ER stress decreased areas of nonperfusion and neovascularization in OIR retinas. As TXNIP/NLRP3 pathway activation has been demonstrated to be involved in increased retinal vascular permeability of ischemic retinopathy, we observed that TXNIP/NLRP3 pathway mediated in the interaction between IL-17A and ER stress under hypoxic conditions. CONCLUSION: The interplay between IL-17A and ER stress contributes to RNV in macrophages via modulation of TXNIP/NLRP3 signaling pathway under hypoxic conditions. The feedback loops may become an innovative and multiple pharmacological therapeutic target for ischemic retinopathy.

Modulation of p75NTR on Mesenchymal Stem Cells Increases Their Vascular Protection in Retinal Ischemia-Reperfusion Mouse Model.

Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and receiving LM11A-31 was assessed by visual-clue water-maze test. I/R significantly increased the number of acellular capillaries (3.2-Fold) in WT retinas, which was partially ameliorated in p75NTR-/- retinas. GFP-MSCs were successfully incorporated and engrafted into retinal vasculature 1 week post injection and normalized the number of acellular capillaries in p75NTR-/- retinas, yet ischemic WT retinas maintained a 2-Fold increase. Silencing p75NTR on GFP-MSCs coincided with a higher number of cells homing to the ischemic WT retinal vasculature and normalized the number of acellular capillaries when compared to ischemic WT retinas receiving scrambled-GFP-MSCs. In vitro, silencing p75NTR-MSCs enhanced their secretome, as evidenced by significant increases in SDF-1, VEGF and NGF release in MSCs conditioned medium; improved paracrine angiogenic response in HREs, where HREs showed enhanced migration (1.4-Fold) and tube formation (2-Fold) compared to controls. In parallel, modulating MSCs-p75NTR using LM11A-31 resulted in a similar improvement in MSCs secretome and the enhanced paracrine angiogenic potential of HREs. Further, intervention with LM11A-31 significantly mitigated the decline in visual acuity post retinal I/R injury. In conclusion, p75NTR modulation can potentiate the therapeutic potential of MSCs to harness vascular repair in ischemic retinopathy diseases.

Matrix Metalloproteinases MMP-2 and MMP-9, Their Inhibitors TIMP-1 and TIMP-2, Vascular Endothelial Growth Factor and sVEGFR-2 as Predictive Markers of Ischemic Retinopathy in Patients with Systemic Sclerosis-Case Series Report.

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder associated with multiple organ involvement. The aim of the study was to present two SSc patients who were diagnosed with ischemic retinopathy in both eyes. As a background to our case study, we decided to investigate the imbalance of angiogenesis factors in 25 SSc patients in relation to 25 healthy controls. Assays of matrix metalloproteinases-2 and -9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1) and -2 (TIMP-2), vascular endothelial growth factor (VEGF), and soluble VEGF receptor-2 (sVEGFR-2) in blood serum and tears were performed. A significantly increased levels of MMP-9 in serum and tears, (p = 0.0375 and p < 0.001, respectively) as well as VEGF/sVEGFR-2 ratio in tears (p < 0.001) were found in the whole SSc patients group compared with controls, while reduced levels of these parameters in patients with ischemic sclerodermic retinopathy were noted. We also observed decreased level MMP-2 in tears and increased levels of TIMP-2 in blood serum and tears of SSc patients with retinal ischemic changes. MMP-9, MMP-2, TIMP-2, and VEGF/sVEGFR-2 may play a crucial role in ischemic retinal degeneration or retinal reorganization in SSc.