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Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets.

ABSTRACT: Diabetic retinopathy (DR), one of the common complications of diabetes, is the leading cause of visual loss in working-age individuals in many industrialized countries. It has been traditionally regarded as a purely microvascular disease in the retina. However, an increasing number of studies have shown that DR is a complex neurovascular disorder that affects not only vascular structure but also neural tissue of the retina. Deterioration of neural retina could precede microvascular abnormalities in the DR, leading to microvascular changes. Furthermore, disruption of interactions among neurons, vascular cells, glia and local immune cells, which collectively form the neurovascular unit, is considered to be associated with the progression of DR early on in the disease. Therefore, it makes sense to develop new therapeutic strategies to prevent or reverse retinal neurodegeneration, neuroinflammation and impaired cell-cell interactions of the neurovascular unit in early stage DR. Here, we present current perspectives on the pathophysiology of DR as a neurovascular disease, especially at the early stage. Potential novel treatments for preventing or reversing neurovascular injuries in DR are discussed as well.

SUBMITTER: Nian S

PROVIDER: S-EPMC8088070 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets.

Nian Shen S Lo Amy C Y ACY Mi Yajing Y Ren Kai K Yang Di D

Eye and vision (London, England) 20210501 1

Diabetic retinopathy (DR), one of the common complications of diabetes, is the leading cause of visual loss in working-age individuals in many industrialized countries. It has been traditionally regarded as a purely microvascular disease in the retina. However, an increasing number of studies have shown that DR is a complex neurovascular disorder that affects not only vascular structure but also neural tissue of the retina. Deterioration of neural retina could precede microvascular abnormalities ...[more]

PMID: 33931128

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Project description:PurposeThe purpose of this study was to explore the succession of the central and peripheral neurovascular and microstructural impairments in patients with full-course diabetic retinopathy (DR), consisting of preclinical DR, nonproliferative DR (NPDR), and proliferative DR (PDR).MethodsOur analysis included 81 participants (including 23 healthy controls, 23 with preclinical DR [diabetes without retinopathy], 13 with NPDR, and 22 with PDR) from the Guangdong Diabetic Retinopathy Multiple Omics Study. Retinal structure and function were evaluated and quantified using ultra-widefield swept-source optical coherence tomography angiography (UWF-SS-OCTA), electroretinography (ERG), and adaptive optics scanning laser ophthalmoscopy (AOSLO). Correlation analysis was conducted to explore the relationship between structural parameters and functional parameters.ResultsIn the preclinical DR group, decreased amplitude in the DR assessment protocol were observed (P = 0.003), with no changes in structure and photoreceptor cells (all P > 0.05). In the NPDR group, photoreceptor cells were impaired (all P < 0.05) with delayed implicit time in the International Society for Clinical Electrophysiology of Vision (ISCEV) Photopic flicker protocol, increased macular and inner nuclear layer thickness, and decreased vessel density and perfusion area of the deep capillary plexus (all P < 0.05). In the PDR group, delayed implicit time and decreased amplitude in the ISCEV Photopic flicker and photopic negative response (PhNR) protocol, and neurovascular impairments were observed (all P < 0.05). Correlation analysis demonstrated a significant correlation between functional parameters and various structural indicators (all P < 0.05).ConclusionsThe cone pathway function began to decline in preclinical DR and distinct photoreceptor cell disorders were observed in NPDR. Notably, instruments with a wider field of view or more detailed microscopic techniques will provide enhanced neurovascular imaging, offering fresh insights into full-course DR.

Project description:BackgroundThis study aimed to identify and evaluate potential molecular targets associated with the development of proliferative diabetic retinopathy (DR).MethodsThe microarray dataset "GSE60436" generated from fibrovascular membranes (FVMs) associated with proliferative DR was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from the active FVMs and control or inactive FVMs and control were evaluated and co-DEGs were identified using VEEN analysis. Functional enrichment analysis, and protein-protein interactions (PPI) network and module analyses were performed on the upregulated and downregulated coDEGs. Finally, several predictions regarding microRNAs (miRNAs) and transcription factors (TFs) were made to construct a putative TF-miRNA-target network.ResultsA total of 1475 co-DEGs were screened in active/inactive FVM samples, including 461 upregulated and 1014 downregulated genes, which were enriched for angiogenesis [Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Placental Growth Factor (PGF)] and visual perception, respectively. In the case of the upregulated co-DEGs, Kinesin Family Member 11 (KIF11), and BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) exhibited the highest values in both the PPI network and module analyses, as well as the genes related to mitosis. In the case of downregulated co-DEGs, several G protein subunits, including G Protein Subunit Beta 3 (GNB3), exhibited the highest values in both the PPI network and module analyses. The genes identified in the module analysis were found to be from the signal transduction-related pathways. In addition, we were able to identify four miRNAs and five TFs, including miR-136 and miR-374.ConclusionsIn brief, HIF1A, PGF, KIF11, G protein subunits, and miR-136, miR-374 may all be involved in angiogenesis, retinal endothelial cell proliferation, and visual signal transduction in proliferative DR. This study provides a number of novel insights that may aid the development of future studies dedicated to discovering novel therapeutic targets in proliferative DR.

Project description:Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the first-line treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor -α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.

Dataset Information

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets.

Publications

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets.

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