Retinal Vascular Leakage Research Articles

Ocular Ischemic Syndrome in the Setting of Normal Carotid Duplex Ultrasound

Purpose: To describe two cases of ocular ischemic syndrome (OIS) that were initially ruled out due to a negative carotid duplex ultrasound (DUS) but eventually confirmed by angiography studies. Methods: Case series. Results: Case 1: A 67-year-old female presented with symptoms suggestive of OIS, but carotid DUS was negative, and the patient was diagnosed with occlusive retinal vasculitis due to retinal non-perfusion and vascular leakage on fluorescein angiography (FA). Immunosuppressive therapy was initiated but her symptoms did not improve. Computerized tomography angiography (CTA) was significant for severe osteal stenosis of the aortic arch vessels. Left common carotid angioplasty and stenting resulted in complete resolution of the symptoms and vascular leakage of the left eye. Case 2: A 41-year-old male with cryoglobulinemia-associated vasculitis complained of symptoms consistent with OIS, which was initially ruled out through a negative carotid DUS. FA revealed delayed arterial filling with poor retinal perfusion. Magnetic resonance angiography (MRA) revealed ophthalmic artery stenosis which was attributed to the underlying systemic vasculitis. Conclusion: CTA or MRA should be performed to rule out OIS if DUS is negative in the setting of high clinical suspicion. Carotid ostial and ophthalmic artery stenoses are rare but possible causes of OIS.

Experimental study on the therapeutic effect and mechanism of erlotinib on non-proliferative diabetic retinopathy

Experimental study on the therapeutic effect and mechanism of erlotinib on non-proliferative diabetic retinopathy

MiR-423-5p promotes Müller cell activation via targeting NGF signaling in diabetic retinopathy

AimsDiabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus and one of the major causes of visual impairment and blindness in industrialized countries. The early neuro-glial perturbations, especially retinal Müller cells (rMC) activation, intimately associated with the vascular alterations. MicroRNAs (miRNAs) have been reported to play critical roles in the progression of DR. Here, we aimed to further explore the role and underlying mechanism of miR-423-5p in Müller cell activation in streptozotocin (STZ)-induced diabetic mice and oxygen-induced retinopathy (OIR) model. Materials and methodsRetinal histology, optical coherence tomography (OCT) and biochemical markers were assessed. Key findingsOur data revealed that the expression of miR-423-5p was significantly increased under high-glucose environment. We also demonstrated that miR-423-5p overexpression markedly accelerated retinal vascular leakage, leukocytosis, and rMC activation. This response was ameliorated in animals pre-treated with the inhibition of miR-423-5p. Specifically, miR-423-5p bound to the nerve growth factor (NGF) 3′ UTR region to induce its silencing. NGF inhibition significantly promoted retinal microvascular dysfunction. SignificanceThese findings demonstrate that miR-423-5p is a critical miRNA that promotes microvascular dysfunction in DR.

Assessment of Inner Blood-Retinal Barrier: Animal Models and Methods.

Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood-retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/β-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs.

A de novo missense mutation in MPP2 confers an increased risk of Vogt–Koyanagi–Harada disease as shown by trio-based whole-exome sequencing

Vogt–Koyanagi–Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease.

FTO fuels diabetes-induced vascular endothelial dysfunction associated with inflammation by erasing m6A methylation of TNIP1.

Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.

MG132, Attenuates the Retinal Vascular Injury Through the Upregulation of Nrf2 Expression.

Purpose: This study clarifies the beneficial effects of MG132, a proteasomal inhibitor, on retinal vascular injury mediated by diabetes-induced oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2). Methods: Diabetic rats and control animals were randomly assigned to receive MG132 or vehicle for 24 weeks, and human retinal endothelial cells (HRECs) were incubated with normal or high glucose with or without MG132. 26S proteasome activity in the rat retinas or cultured HRECs was measured using Suc-LLVY-7-amido-4-methylcoumarin. NADPH-quinone oxidoreduc-tase (NQO1), heme oxygenase (HO)-1, kelch-like ECH-associated protein 1 (Keap1) and Nrf2 were examined by Western blotting and real-time reverse transcription polymerase chain reaction. Cell apoptosis is measured through flow cytometry assay, mitochondrial reactive oxygen species (ROS) production, and retinal vascular leakage were assayed using CM-H2DCFDA fluorescent probes and Evans blue, respectively. Results: MG132 significantly inhibited the activation of 26S proteasome induced by diabetes or elevated glucose, and subsequently increased the expression of Nrf2, NQO1, and HO-1, and further reduced ROS accumulation. These changes were associated with a decrease of diabetes-induced retinal vascular leakage and retinal capillary cell apoptosis. Conclusions: MG132 decreases diabetes-induced 26S proteasome activation and exerts protective effects against retinal microvascular dysfunction in diabetic rats in association with the alleviation of retinal oxidative stress mediated by Nrf2.

Treatment of Intermediate Uveitis-associated Retinal Vasoproliferative Tumors: A Case Series.

To report the use of combination intravitreal pharmacotherapy using anti-vascular endothelial growth factor (VEGF) and short and long-term corticosteroid implants for the treatment of retinal vasoproliferative tumors (VPT) associated with intermediate uveitis. Retrospective chart review of patients with VPT secondary to idiopathic intermediate uveitis that underwent combination intravitreal pharmacotherapy at a single center was performed. Multimodal imaging including ultrawide field color fundus photography, ultrawide field fluorescein angiography, and optical coherence tomography obtained before and after treatment were reviewed. Four eyes of 4 patients were treated with multiple injections of a combination of aflibercept, dexamethasone, and fluocinolone acetonide implants for VPT associated with intermediate uveitis. All 4 patients had improvement in visual acuity, intraocular inflammation, central macular thickness, and retinal vascular leakage, as well as regression of the VPT and reduction in lesion leakage on follow-up. Combination intravitreal anti-VEGF and corticosteroid implants may be a useful approach for the treatment of intermediate uveitis-associated VPTs and can lead to both functional and structural improvement.

TGR5 supresses cGAS/STING pathway by inhibiting GRP75-mediated endoplasmic reticulum-mitochondrial coupling in diabetic retinopathy

Diabetic retinopathy (DR) is a serious and relatively under-recognized complication of diabetes. Müller glial cells extend throughout the retina and play vital roles in maintaining retinal homeostasis. Previous studies have demonstrated that TGR5, a member of the bile acid-activated GPCR family, could ameliorate DR. However, the role of TGR5 in regulating Müller cell function and the underlying mechanism remains to be ascertained. To address this, high glucose (HG)-treated human Müller cells and streptozotocin-treated Sprague-Dawley rats were used in the study. The IP3R1-GRP75-VDAC1 axis and mitochondrial function were assessed after TGR5 ablation or agonism. Cytosolic mitochondrial DNA (mtDNA)-mediated cGAS-STING activation was performed. The key markers of retinal vascular leakage, apoptosis, and inflammation were examined. We found that mitochondrial Ca2+ overload and mitochondrial dysfunction were alleviated by TGR5 agonist. Mechanically, TGR5 blocked the IP3R1-GRP75-VDAC1 axis mediated Ca2+ efflux from the endoplasmic reticulum into mitochondria under diabetic condition. Mitochondrial Ca2+ overload led to the opening of the mitochondrial permeability transition pore and the release of mitochondrial DNA (mtDNA) into the cytosol. Cytoplasmic mtDNA bound to cGAS and upregulated 2’3’ cyclic GMP-AMP. Consequently, STING-mediated inflammatory responses were activated. TGR5 agonist prevented retinal injury, whereas knockdown of TGR5 exacerbated retinal damage in DR rats, which was rescued by the STING inhibitor. Based on the above results, we propose that TGR5 might be a novel therapeutic target for the treatment of DR.

Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders.

Vascular endothelial growth factors (VEGFs) are key mediator of retinal and choroidal neovascularization as well as retinal vascular leakage leading to macular edema. As such, VEGF plays an important role in mediating visually significant complications associated with common retinal disorders such as diabetic retinopathy, retinal vein occlusion, and age-related macular degeneration. Various drugs that inhibit vascular endothelial growth factors (anti-VEGF therapies) have been developed to minimize vision loss associated with these disorders. These drugs are injected into the vitreous cavity in a clinic setting at regular intervals. This article provides an overview of the various anti-VEGF drugs used in ophthalmology and the common retinal conditions that benefit from this therapy.

The hsa_circ_0004805/hsa_miR-149-5p/TGFB2 axis plays critical roles in the pathophysiology of diabetic retinopathy in vitro and in vivo

The aim of this study was to investigate the mechanism underlying the role of a recently identified hsa_circ_0004805/hsa_miR-149-5p/transforming growth factor beta 2 (TGFB2) axis in the progression of diabetic retinopathy (DR). Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis suggested that hsa_circ_0004805 was highly expressed in aqueous humor samples of patients with DR, whereas hsa_miR-149-5p showed the opposite trend. Meanwhile, the results of a dual-luciferase reporter assay indicated that hsa_miR-149-5p directly interacted with both hsa_circ_0004805 and TGFB2. Using a variety of assays (Cell Counting Kit-8, EdU-labeling, Transwell, flow cytometric, wound healing, tube formation assays), we found that the overexpression of hsa_circ_0004805 significantly downregulated the level of hsa_miR-149-5p and promoted DNA synthesis, proliferation, migration, and tube formation in human retinal microvascular epithelial cells (hRECs) cultivated in a high-glucose environment. In contrast, hsa_miR-149-5p mimics inhibited DNA synthesis, proliferation, migration, and tube formation in hRECs by reducing the expression of its downstream target TGFB2 as well as the levels of phosphorylated SMAD2; however, these effects were reversed by the overexpression of hsa_circ_0004805. In a streptozotocin-induced Sprague-Dawley rat model of DR, retinal vascular leakage, capillary decellularization, loss of pericytes, fibrosis, and gliosis were evident, which could be reversed by vitreous microinjection of rat miR-149-5p mimics (rno-miR-149-5p agomir). Combined, our findings indicated that, under hyperglycemia, the hsa_circ_0004805/hsa_miR-149-5p/TGFB2 axis plays a critical role in the retinal pathophysiology associated with the development of DR, and has potential as a therapeutic target in the treatment of this condition.

The circRNA MKLN1 regulates autophagy in the development of diabetic retinopathy

Diabetic retinopathy (DR) is a common complication in patients with diabetes and has become an important cause of blindness in working-age people. However, the mechanisms involved have not been fully elucidated. Circular RNAs (circRNAs) can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: the competing endogenous RNA (ceRNA) model. We isolated total RNA from extracellular vesicles in the serum of healthy individuals (Con) and individuals with diabetes mellitus without DR (DM), nonproliferative DR (NPDR), or proliferative DR (PDR) and subjected them to deep sequencing. We found aberrantly high expression of circMKLN1. In a streptozotocin (STZ)-induced mice model of diabetes, the inhibition of circMKLN1 with AAV2 transduction markedly ameliorated retinal acellular vessels and vascular leakage, which was reversed by intravitreal injection of rapamycin, a potent autophagy inducer. In addition, circMKLN1 adsorbs miR-26a-5p as a molecular sponge and mediates high glucose (HG)/methylglyoxal (MG)-induced autophagy in hRMECs. CircMKLN1-silencing treatment reduces HG/MG-related reactive autophagy and inflammation. In addition, miR-26a-5p targeting by circMKLN1 plays an important role in the regulation of Rab11a expression. Thus, either new biomarkers or new therapeutic targets may be identified with the translation of these findings.

New retinal findings in NLRP3-associated autoinflammatory disease

PurposeTo determine whether the rare NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) is associated with retinal changes and to assess the ocular involvement.MethodsA retrospective cohort study of 20 patients(40 eyes) diagnosed with rare NLRP3-AID at Peking Union Medical College Hospital, from April 2015 to August 2022. Patients underwent a comprehensive ophthalmological examination, including visual acuity, intraocular pressure examination, slit-lamp examination, fundus photography, optical coherence tomography(OCT), and fluorescence angiography (FA). Some patients also underwent optical coherence tomography angiography (OCTA).ResultsThis study analyzed 40 eyes of 20 patients (11 [55.0%] male; median age, 25.0 years [range, 12–52 years]) and 13 patients (26 eyes, 65%) demonstrated ocular involvement. The most common ophthalmologic manifestation was conjunctivitis (22 eyes, 84.6%), followed by papilledema (14 eyes, 53.8%), retinopathy (10 eyes, 38.5%), optic atrophy (6 eyes, 23.1%), uveitis (4 eyes, 15.4%), reduced pupil light reflex (3 eyes, 11.5%) and cataracts (2 eyes, 7.7%). Ocular involvement was bilateral in 11 patients (55.0%). Five kinds of retinal lesions were seen in 5 patients (10 eyes, 25%) with NLRP3-AID, including peripheral retinal vascular leakage, microaneurysms, macular ischemia, macular epiretinal membrane formation and drusen.ConclusionsPeripheral retinal vascular leakage, macular ischemia, microaneurysms and drusen are newly identified retinal findings in patients with NLRP3-AID, which suggests the importance of detailed retinal examination in these patients.

The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy

BackgroundIn diabetic retinopathy, increasing evidence points to a link between the pathogenesis of retinal microangiopathy and the endothelial cell-specific factor roundabout4 (ROBO4). According to earlier research, specificity protein 1 (SP1) enhances the binding to the ROBO4 promoter, increasing Robo4 expression and hastening the progression of diabetic retinopathy. To determine if this is related to aberrant epigenetic modifications of ROBO4, we examined the methylation level of the ROBO4 promoter and the corresponding regulatory mechanism during the course of diabetic retinopathy and explored the effect of this mechanism on retinal vascular leakage and neovascularization.MethodsThe methylation level of CpG sites in the ROBO4 promoter was detected in human retinal endothelial cells (HRECs) cultured under hyperglycemic conditions and retinas from streptozotocin-induced diabetic mice. The effects of hyperglycemia on DNA methyltransferase 1, Tet methylcytosine dioxygenase 2 (TET2), 5-methylcytosine, 5-hydroxymethylcytosine, and the binding of TET2 and SP1 to the ROBO4 promoter, as well as the expression of ROBO4, zonula occludens 1 (ZO-1) and occludin were examined. Short hairpin RNA was used to suppress the expression of TET2 or ROBO4 and the structural and functional changes in the retinal microvascular system were assessed.ResultsIn HRECs cultured under hyperglycemic conditions, the ROBO4 promoter methylation level decreased. Hyperglycemia-induced TET2 overexpression caused active demethylation of ROBO4 by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, which enhanced the binding of SP1 to ROBO4, increased the expression of ROBO4, and decreased the expression of ZO-1 and occludin, leading to the abnormalities in monolayer permeability, migratory ability and angiogenesis of HRECs. The above pathway was also demonstrated in the retinas of diabetic mice, which caused leakage from retinal capillaries and neovascularization. Inhibition of TET2 or ROBO4 expression significantly ameliorated the dysfunction of HRECs and retinal vascular abnormalities.ConclusionsIn diabetes, TET2 can regulate the expression of ROBO4 and its downstream proteins by mediating active demethylation of the ROBO4 promoter, which accelerates the development of retinal vasculopathy. These findings suggest that TET2-induced ROBO4 hypomethylation is a potential therapeutic target, and anti- TET2/ROBO4 therapy is anticipated to emerge as a novel strategy for early intervention and delayed progression of diabetic retinopathy.

Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy.

Diabetic retinopathy (DR), a leading cause of vision loss in working-age adults, induces mosaic patterns of vasculopathy that may be associated with spatial heterogeneity of intraretinal endothelial cells. We recently reported that secretogranin III (Scg3), a neuron-derived angiogenic and vascular leakage factor, selectively binds retinal vessels of diabetic but not healthy mice. Here, we investigated endothelial heterogeneity of three retinal vascular plexuses in DR pathogenesis and the therapeutic implications. Our unique in vivo ligand binding assay detected a 22.7-fold increase in Scg3 binding to retinal vessels of diabetic mice relative to healthy mice. Functional immunohistochemistry revealed that Scg3 predominantly binds to the DR-stressed CD31- deep retinal vascular plexus but not to the relatively healthy CD31+ superficial and intermediate plexuses within the same diabetic retina. In contrast, VEGF bound to healthy and diabetic retinal vessels indiscriminately with low activity. FITC-dextran assays indicated that selectively increased retinal vascular leakage coincides with Scg3 binding in diabetic mice that was independent of VEGF, whereas VEGF-induced leakage did not distinguish between diabetic and healthy mice. Dose-response curves showed that the anti-Scg3 humanized antibody (hAb) and anti-VEGF aflibercept alleviated DR leakage with equivalent efficacies, and that the combination acted synergistically. These findings suggest: (i) the deep plexus is highly sensitive to DR; (ii) Scg3 binding to the DR deep plexus coincides with the loss of CD31 and compromised endothelial junctions; (iii) anti-Scg3 hAb alleviates vascular leakage by selectively targeting the DR-stressed deep plexus within the same diabetic retina; (iv) combined anti-Scg3 and anti-VEGF treatments synergistically ameliorate DR through distinct mechanisms.

Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.

Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation. We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries. In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration. These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials.

MicroRNA 9 Is a Regulator of Endothelial to Mesenchymal Transition in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a significant cause of blindness. Most research around DR focus on late-stage developments rather than early changes such as early endothelial dysfunction. Endothelial-to-mesenchymal transition (EndMT), an epigenetically regulated process whereby endothelial cells lose endothelial characteristics and adopt mesenchymal-like phenotypes, contributes to early endothelial changes in DR. The epigenetic regulator microRNA 9 (miR-9) is suppressed in the eyes during DR. MiR-9 plays a role in various diseases and regulates EndMT-related processes in other organs. We investigated the role miR-9 plays in glucose-induced EndMT in DR. We examined the effects of glucose on miR-9 and EndMT using human retinal endothelial cells (HRECs). We then used HRECs and an endothelial-specific miR-9 transgenic mouse line to investigate the effect of miR-9 on glucose-induced EndMT. Finally, we used HRECs to probe the mechanisms through which miR-9 may regulate EndMT. We found that miR-9 inhibition was both necessary and sufficient for glucose-induced EndMT. Overexpression of miR-9 prevented glucose-induced EndMT, whereas suppressing miR-9 caused glucose-like EndMT changes. We also found that preventing EndMT with miR-9 overexpression improved retinal vascular leakage in DR. Finally, we showed that miR-9 regulates EndMT at an early stage by regulating EndMT-inducing signals such as proinflammatory and TGF-β pathways. We have shown that miR-9 is an important regulator of EndMT in DR, potentially making it a good target for RNA-based therapy in early DR.

A 48-year-old female with chronic, progressive bilateral vision loss and dyspnea.

To describe a unique case of isolated, bilateral serous retinal detachments associated with primary pulmonary arterial hypertension. Case report. A 48-year-old woman with primary pulmonary arterial hypertension presented with bilateral vision loss. She was found to have bilateral serous retinal detachments in the macula with accumulation of the fibrinous material. Optical coherence tomography demonstrated intraretinal and subretinal fluid, hyperreflective material in the subretinal space, and choroidal engorgement. Fluorescein angiography demonstrated pooling in the maculas, an area of blockage corresponding with the area of subretinal exudative material, and a petalloid pattern of leakage in the maculas without evidence of retinal vascular leakage. Her ocular symptoms improved with aggressive medical management of her pulmonary arterial hypertension with the addition of eplerenone. Primary pulmonary arterial hypertension results in chronically elevated systemic venous pressure, leading to both systemic and ocular symptoms. It is important to consider this systemic condition in the differential diagnosis of serous retinal detachments to provide adequate multidisciplinary management.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy

Diabetic retinopathy (DR) is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults. The high levels of glucose trigger multiple intracellular oxidative stress pathways, such as POLDIP2, resulting in excessive reactive oxygen species (ROS) production and increased expression of vascular cell adhesion molecule-1 (VCAM-1), hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF), causing microvascular dysfunction. Dihydromyricetin (DMY) is a natural flavonoid small molecule antioxidant. However, it exhibits poor solubility in physiological environments, has a short half-life in vivo, and has low oral bioavailability. In this study, we present, for the first time, the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles (Fe-DMY NCPs), formed by combining DMY with low-toxicity iron ions. In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose, scavenge excess ROS, and improve pathological features of DR, such as retinal vascular leakage and neovascularization. Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H2O2 signaling pathway and downregulate vital vascular function indicators such as VCAM-1, HIF-1α, and VEGF. These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent, with the potential as a novel multimeric drug for DR therapy.

Familial exudative vitreoretinopathy with retinitis pigmentosa

Familial exudative vitreoretinopathy (FEVR) is a rare inherited slowly progressive disorder characterized by failure of vascularization of the peripheral retina and poor vascular differentiation. Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous inherited retinal disorders characterized by diffuse progressive dysfunction of predominantly rod photoreceptors with subsequent involvement of cone photoreceptors. A 13-year-old boy presented with nyctalopia and low vision for 10 years. Fundus evaluation showed retinal pigmentary changes in the mid-periphery. The fundus fluorescein angiogram showed straightening of retinal vessels, vascular leakage, and avascularity of the peripheral retina, suggestive of FEVR. Full-field electroretinogram (FFERG) showed grossly reduced scotopic and photopic responses in both eyes, pointing toward retinitis pigmentosa (RP). To the best of our knowledge, this case is the second one internationally, and the first in India to show the coexistence of FEVR and RP in the same patient.