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10 pages, 3073 KiB

Open AccessArticle

Juxtavascular Microglia Scavenge Dying Pericytes and Vascular Smooth Muscle Cells in Diabetic Retinopathy

by Tom A. Gardiner and Alan W. Stitt

Int. J. Transl. Med. 2022, 2(1), 41-50; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm2010004 - 19 Jan 2022

Cited by 2 | Viewed by 2464

Diabetic retinopathy (DR) remains a prevalent complication of diabetes and a major cause of vision loss among the working population. Selective loss of pericytes and vascular smooth muscle cells (SMCs), the mural cells of the retinal blood vessels, is pathognomonic of the vasodegenerative [...] Read more.

Diabetic retinopathy (DR) remains a prevalent complication of diabetes and a major cause of vision loss among the working population. Selective loss of pericytes and vascular smooth muscle cells (SMCs), the mural cells of the retinal blood vessels, is pathognomonic of the vasodegenerative element of diabetic retinopathy, and recent studies suggest a central role for autophagy-dependent cell death in this pathology. Our first study of archival electron micrographs from diabetic donor retina provided evidence for the involvement of autophagy in mural cell death during DR and the current report extends those observations to the fate of mural cell corpses in the vascular wall. Here we show that the efferocytosis, or phagocytic removal of dying mural cells, is carried out by a population of juxtavascular microglia (JVM). This population of microglia are well-characterised in the brain but previously unreported in the retina. We demonstrate that JVM are distinct from perivascular macrophages as they participate in the glia limitans of the retinal vasculature and constitute an integral component of the neurovascular unit of the retina. Importantly, mural cells undergoing active phagocytic engulfment appeared to represent relatively early stages in autophagy-dependent cell death, suggesting that the more degraded pericyte and SMC corpses, known as “ghosts”, have evaded efficient efferocytosis and undergone secondary necrosis. The alternative fates of mural cell corpses in the retinal vasculature may have important implications for inflammatory processes in the vasodegenerative pathology characteristic of DR. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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15 pages, 4825 KiB

Open AccessArticle

Pericyte and Vascular Smooth Muscle Death in Diabetic Retinopathy Involves Autophagy

by Tom A. Gardiner and Alan W. Stitt

Int. J. Transl. Med. 2022, 2(1), 26-40; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm2010003 - 19 Jan 2022

Cited by 3 | Viewed by 2971

Abstract

Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of vision loss worldwide. The premature death of the microvascular mural cells represents both a pathological hallmark of vasodegeneration in DR and a basis for therapeutic intervention to halt [...] Read more.

Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of vision loss worldwide. The premature death of the microvascular mural cells represents both a pathological hallmark of vasodegeneration in DR and a basis for therapeutic intervention to halt progression to the sight-threatening stages. Recent studies suggest that retinal microvascular mural cells, classed as pericytes in the capillaries and vascular smooth muscle cells in the larger vessels (VSMC), may undergo autophagy-dependent cell death during DR. The present investigation was undertaken to assess electron microscopic evidence for involvement of autophagy in mediation of cell death in the mural cells of the retinal vasculature, in eyes from human diabetic donors and diabetic dogs. All specimens examined showed widespread evidence of autophagosomes in processes of viable pericytes and VSMCs, and the membranous remnants of excessive autophagic activity in their “ghost cell” remnants within the vascular walls. Autophagy was termed “excessive” when it occupied the greater part of the cytoplasm in mural cell processes. This was notable in specimens from short-term diabetic donors with no evidence of basement-membrane thickening or mural cell loss, in which regions of mural cell cytoplasm filled with autophagic bodies appeared to be undergoing cytoplasmic cleavage. No equivalent evidence of autophagy was detected in the adjacent endothelial cells of the retinal vessels. We conclude that increased autophagy in the retinal pericytes and VSMCs is linked to the diabetic milieu, and over time may also act as a trigger for mural cell loss and progressive vasodegeneration. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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9 pages, 253 KiB

Open AccessArticle

Diabetic Retinopathy Screening Programme: Attendance, Barriers and Enablers amongst Young People with Diabetes Mellitus Aged 12–26 Years

by Laura N. Cushley, Katie Curran, Nicola B. Quinn, Aaron Bell, Alyson Muldrew, Una M. Graham, David R. McCance, Qing Wen and Tunde Peto

Int. J. Transl. Med. 2021, 1(3), 154-162; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1030011 - 22 Sep 2021

Viewed by 2764

Abstract

The study aim is to investigate characteristics, barriers and enablers for attendance at the Diabetic Eye Screening Programme Northern Ireland (DESPNI) among people with diabetes aged 12–26 years. A mixed-methods approach with retrospective analysis and prospective, questionnaire-based data collection was completed. Data were [...] Read more.

The study aim is to investigate characteristics, barriers and enablers for attendance at the Diabetic Eye Screening Programme Northern Ireland (DESPNI) among people with diabetes aged 12–26 years. A mixed-methods approach with retrospective analysis and prospective, questionnaire-based data collection was completed. Data were analysed using ordinal logistic regression. A questionnaire collected information on barriers and enablers to attending DESPNI. Age, diabetes duration, attendance at diabetes clinic and lower HbA1c values were significantly associated with better attendance. Those aged 12–15 were more likely to attend screening than 16–26 years, odds ratio (OR) 4.01. Subjects diagnosed less than 5 years were more likely to attend than those with longer diabetes duration (OR = 2.52, p =< 0.001). Subjects who attended diabetes clinics were more likely to attend screening (OR = 1.89, p =< 0.001) and have a lower HbA1c (OR = 1.46, p =< 0.001). Questionnaires revealed major barriers to attendance which included inconvenient appointment times, lack of access and poor communication. While many subjects were aware of the impact of diabetes on the eye, many had little understanding of screening. This study provides pivotal information on potential barriers and enablers for young people attending eye screening. We suggest modest changes such as convenient appointment times, clearer communication and one-stop clinics could improve attendance. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

18 pages, 2995 KiB

Open AccessArticle

Interleukin-6 Trans-Signaling Mediated Regulation of Paracellular Permeability in Human Retinal Endothelial Cells

by Joshua Glass, Rebekah Robinson, Tae-Jin Lee, Ashok Sharma and Shruti Sharma

Int. J. Transl. Med. 2021, 1(2), 137-153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1020010 - 16 Sep 2021

Cited by 1 | Viewed by 3435

Abstract

Long-term hyperglycemia-mediated oxidative stress and inflammation lead to the blood-retinal barrier (BRB) dysfunction and increased vascular permeability associated with diabetic retinopathy (DR). Interleukin-6 (IL-6) is one of the primary mediators of retinal vascular inflammation. IL-6 signaling through its membrane-bound IL-6 receptor is known [...] Read more.

Long-term hyperglycemia-mediated oxidative stress and inflammation lead to the blood-retinal barrier (BRB) dysfunction and increased vascular permeability associated with diabetic retinopathy (DR). Interleukin-6 (IL-6) is one of the primary mediators of retinal vascular inflammation. IL-6 signaling through its membrane-bound IL-6 receptor is known as classical signaling, and through a soluble IL-6 receptor (sIL-6R) is known as trans-signaling. Increasing evidence suggests that classical signaling is primarily anti-inflammatory, whereas trans-signaling induces the pro-inflammatory effects of IL-6. The purpose of this study was to compare the effects of these two pathways on paracellular permeability and expression of genes involved in inter-endothelial junctions in human retinal endothelial cells (HRECs). IL-6 trans-signaling activation caused significant disruption to paracellular integrity, with increased paracellular permeability, and was associated with significant changes in gene expression related to adherens, tight, and gap junctions. IL-6 classical signaling did not alter paracellular resistance in HRECs and had no distinct effects on gene expression. In conclusion, IL-6 trans-signaling, but not classical signaling, is a major mediator of the increased paracellular permeability characteristic of inner BRB breakdown in diabetic retinopathy. This study also identified potential inter-endothelial junction genes involved in the IL-6 trans-signaling mediated regulation of paracellular permeability in HRECs. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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14 pages, 2691 KiB

Open AccessArticle

Toll-Like Receptor Signalling Pathways Regulate Hypoxic Stress Induced Fibroblast Growth Factor but Not Vascular Endothelial Growth Factor-A in Human Microvascular Endothelial Cells

by Rukhsar Akhtar, Husain Tahir, Elizabeth Stewart, Ruoxin Wei, Imran Mohammed and Winfried M. Amoaku

Int. J. Transl. Med. 2021, 1(1), 25-38; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1010003 - 27 May 2021

Cited by 1 | Viewed by 3382

Abstract

Retinal diseases are the leading causes of irreversible blindness worldwide. The role of toll-like receptor (TLR) signalling mechanisms (MyD88 and TRIF) in the production of pro-angiogenic growth factors from human microvascular endothelial cells (HMEC-1) under hypoxic stress remains unexplored. HMEC-1 was incubated under [...] Read more.

Retinal diseases are the leading causes of irreversible blindness worldwide. The role of toll-like receptor (TLR) signalling mechanisms (MyD88 and TRIF) in the production of pro-angiogenic growth factors from human microvascular endothelial cells (HMEC-1) under hypoxic stress remains unexplored. HMEC-1 was incubated under normoxic (5% CO₂ at 37 °C) and hypoxic (1% O₂, 5% CO₂, and 94% N₂; at 37 °C) conditions for 2, 6, 24, and 48 h, respectively. For TLR pathway analysis, HMEC-1 was pre-treated with pharmacological inhibitors (Pepinh-MyD88 and Pepinh-TRIF) and subjected to normoxia and hypoxia conditions. Gene and protein expressions of vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor (FGF-2), hypoxia inducible factor 1-alpha (HIF1-α) were performed using quantitative polymerase chain reaction (qPCR), ELISA, and Western blot methodologies. Levels of TLR3 and TLR4 were analysed by flow cytometry. Under hypoxia, levels of VEGF-A and FGF-2 were elevated in a time-dependent fashion. Inhibition of MyD88 and TRIF signalling pathways decreased FGF-2 levels but failed to modulate the secretion of VEGF-A from HMEC-1. Blocking a known regulator, endothelin receptor (ETR), also had no effect on VEGF-A secretion from HMEC-1. Overall, this study provides the proof-of-concept to target TLR signalling pathways for the management of blinding retinal diseases. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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Review

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16 pages, 619 KiB

Open AccessReview

Early Neural Changes as Underlying Pathophysiological Mechanism in Diabetic Retinopathy

by Antolín Cantó, Javier Martínez, Giuliana Perini-Villanueva, María Miranda and Eloy Bejarano

Int. J. Transl. Med. 2022, 2(1), 1-16; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm2010001 - 30 Dec 2021

Cited by 1 | Viewed by 2732

Abstract

Diabetes mellitus is a chronic disease often accompanied by diabetic retinopathy (DR), one of the most common diabetic complications. DR is an eye condition that causes vision deficiency and often leads to blindness. DR develops when blood vessels damage the retina, the light-sensitive [...] Read more.

Diabetes mellitus is a chronic disease often accompanied by diabetic retinopathy (DR), one of the most common diabetic complications. DR is an eye condition that causes vision deficiency and often leads to blindness. DR develops when blood vessels damage the retina, the light-sensitive tissue at the back of the eye. Before changes in retinal blood vessel permeability, different molecular and anatomical modifications take place in the retina, including early neural changes. This review will summarize the current status of knowledge regarding pathophysiological mechanisms underlying DR, with a special focus on early neural modifications associated with DR. We describe hyperglycemia-associated molecular and cellular alterations linked to the initiation and progression of DR. We also discuss retinal neurodegeneration as a shared feature in different in vitro and in vivo models of DR. Given how ubiquitous diabetes is and how severe the effects of DR are, we also examine the current pharmacological and genetic approaches for combatting this disease. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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21 pages, 20870 KiB

Open AccessReview

Developments in Non-Invasive Imaging to Guide Diagnosis and Treatment of Proliferative Diabetic Retinopathy: A Systematic Review

by Ellie Bowditch, Andrew Chang and Hemal Mehta

Int. J. Transl. Med. 2021, 1(3), 332-352; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1030020 - 26 Nov 2021

Cited by 1 | Viewed by 2573

Abstract

Diagnosis and management of proliferative diabetic retinopathy are reliant upon retinal imaging. A systematic literature review of non-invasive imaging to guide diagnosis and treatment of proliferative diabetic retinopathy was performed. There is a trend of moving away from invasive (e.g., fundus fluorescein angiography) [...] Read more.

Diagnosis and management of proliferative diabetic retinopathy are reliant upon retinal imaging. A systematic literature review of non-invasive imaging to guide diagnosis and treatment of proliferative diabetic retinopathy was performed. There is a trend of moving away from invasive (e.g., fundus fluorescein angiography) to non-invasive (e.g., wide-field optical coherence tomography (OCT), OCT angiography and colour fundus photography) imaging modalities to allow for more objective assessments that can be readily repeated in a time-efficient manner without compromising patient safety. Such quantitative assessments generating large amounts of data could benefit from artificial intelligence approaches to aid clinical decision making. These non-invasive imaging modalities continue to improve both in terms of the quality of image acquisition and progress in image interpretation. It is important that newer non-invasive imaging modalities are appropriately validated in large-scale prospective observational studies or randomised clinical trials. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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17 pages, 2723 KiB

Open AccessReview

Nanomedicine for Treating Diabetic Retinopathy Vascular Degeneration

by Tatiana Borodina, Dmitry Kostyushev, Andrey A. Zamyatnin, Jr. and Alessandro Parodi

Int. J. Transl. Med. 2021, 1(3), 306-322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1030018 - 24 Nov 2021

Cited by 3 | Viewed by 3578

Abstract

The incidence of diabetes and the pathological conditions associated with chronic hyperglycemia is increasing worldwide. Among them, diabetic retinopathy represents a leading cause of vision loss, causing a significant structural and functional impairment of the retinal and choroidal capillary network. Current therapies include [...] Read more.

The incidence of diabetes and the pathological conditions associated with chronic hyperglycemia is increasing worldwide. Among them, diabetic retinopathy represents a leading cause of vision loss, causing a significant structural and functional impairment of the retinal and choroidal capillary network. Current therapies include anti-angiogenic and anti-inflammatory drugs administered through repetitive and invasive intraocular injections, and associated with significant adverse effects. The presence of ocular barriers affects the efficiency of topically administered therapeutics for treating the posterior segment of the eye. In this scenario, nanomedicine could improve current therapies for diabetic retinopathy by providing tools that can decrease the number of injections thanks to their controlled release properties, while some materials showed a natural ability to mitigate pathological neo-angiogenesis. Moreover, specific surface modifications could open new scenarios for the development of topical treatments. This review describes current advances in generating nanomedicine for diabetic retinopathy, focusing on the properties of the different materials tested explicitly for this purpose. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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20 pages, 3275 KiB

Open AccessReview

Review of OCT Angiography Findings in Diabetic Retinopathy: Insights and Perspectives

by John Moir, Saira Khanna and Dimitra Skondra

Int. J. Transl. Med. 2021, 1(3), 286-305; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1030017 - 16 Nov 2021

Cited by 3 | Viewed by 7421

Abstract

Diabetes mellitus (DM), a disorder rapidly growing in prevalence, is linked to the retinal microvasculature complication diabetic retinopathy (DR). As one of the leading global causes of vision impairment and loss, imaging techniques to detect and monitor DR must continue to improve in [...] Read more.

Diabetes mellitus (DM), a disorder rapidly growing in prevalence, is linked to the retinal microvasculature complication diabetic retinopathy (DR). As one of the leading global causes of vision impairment and loss, imaging techniques to detect and monitor DR must continue to improve in order to address this growing burden. Optical coherence tomography angiography (OCTA) is a nascent imaging modality that generates three-dimensional visualizations of the retinal and choroidal microvasculature. Compared to fluorescein angiography, the gold-standard imaging modality for retinal vessels, OCTA offers the advantages of being non-invasive, quick, and able to resolve the multiple plexuses within the retina. Quantitative OCTA studies have explored parameters such as vessel density (VD), foveal avascular zone (FAZ), acircularity index, vessel tortuosity (VT), and fractal dimension (FD) amongst DR patients. This review synthesizes the main trends emerging from quantitative OCTA-based studies of DR and interrogates them within the context of DR pathophysiology. We offer a glimpse into how analysis techniques have shifted in the years since OCTA came into existence, while speculating on its future role in clinical practice. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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12 pages, 718 KiB

Open AccessReview

Challenges in Diabetic Micro-Complication Management: Focus on Diabetic Neuropathy

by Prawej Ansari, J.M.A. Hannan, Shofiul Azam and Md. Jakaria

Int. J. Transl. Med. 2021, 1(3), 175-186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijtm1030013 - 06 Oct 2021

Cited by 5 | Viewed by 4765

Abstract

The progression of diabetes leads to macro and microvascular complications, including diabetic neuropathy, which is the most prevalent microvascular complication with diabetes. Clinical manifestations of diabetic neuropathy begin with the loss of distal sensory function, pain, and substantial morbidity. It has been evident [...] Read more.

The progression of diabetes leads to macro and microvascular complications, including diabetic neuropathy, which is the most prevalent microvascular complication with diabetes. Clinical manifestations of diabetic neuropathy begin with the loss of distal sensory function, pain, and substantial morbidity. It has been evident that ~50% of diabetic patients develop neuropathy at a certain stage in their lifetime. Interestingly, two major subtypes (type I and II) of diabetes do not share the same epidemiology and pathophysiology of diabetic neuropathy; thus, their management or treatment strategies may vary from each other. The past few decades of research suggest that many etiological features, diagnosis, and management complexities depend on the type of diabetes. However, the underlying mechanism of neuropathy in type I and type II diabetes remains unclear. This review provides the current knowledge on successful assessment, management, and pharmacological biomarkers to explore the treatment and surpass current challenges in diabetic neuropathy. Full article

(This article belongs to the Special Issue Diabetic Retinopathy)

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