International Journal of Molecular Sciences

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13 pages, 2852 KiB

Open AccessArticle

Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy

by Albert L Lin, Richard J Roman, Kathleen A Regan, Charlotte A Bolch, Ching-Jygh Chen and Siva S.R. Iyer

Int. J. Mol. Sci. 2020, 21(20), 7451; https://doi.org/10.3390/ijms21207451 - 9 Oct 2020

Cited by 15 | Viewed by 3010

Abstract

Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative [...] Read more.

Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative diabetic retinopathy versus controls. The results indicated that lipoxygenase and cytochrome P450-derived eicosanoids were elevated (5-HETE, 12-HETE, 20-HETE, and 20-COOH-AA), and there appeared to be no differences in levels measured in eyes with tractional retinal detachments versus those without. These results provide further insight into the pathogenesis of this disease and for the development of future potential therapeutic agents that target arachidonic acid metabolites to treat diabetic retinopathy. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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17 pages, 3820 KiB

Open AccessArticle

Pemafibrate Protects Against Retinal Dysfunction in a Murine Model of Diabetic Retinopathy

by Yohei Tomita, Deokho Lee, Yukihiro Miwa, Xiaoyan Jiang, Masayuki Ohta, Kazuo Tsubota and Toshihide Kurihara

Int. J. Mol. Sci. 2020, 21(17), 6243; https://doi.org/10.3390/ijms21176243 - 28 Aug 2020

Cited by 36 | Viewed by 5590

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, [...] Read more.

Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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12 pages, 1405 KiB

Open AccessArticle

Impairment of Autophagy Causes Superoxide Formation and Caspase Activation in 661 W Cells, a Cell Line for Cone Photoreceptors, under Hyperglycemic Conditions

by Koichiro Taki, Taeko Horie, Teruyo Kida, Masashi Mimura, Tsunehiko Ikeda and Hidehiro Oku

Int. J. Mol. Sci. 2020, 21(12), 4240; https://doi.org/10.3390/ijms21124240 - 14 Jun 2020

Cited by 16 | Viewed by 3016

Abstract

Microvascular changes are the earliest adverse events in diabetic retinopathy, but recent studies have shown that oxidative stress induced by photoreceptors is associated with the development of the retinopathy. The purpose of this study was to determine the roles played by superoxides formed [...] Read more.

Microvascular changes are the earliest adverse events in diabetic retinopathy, but recent studies have shown that oxidative stress induced by photoreceptors is associated with the development of the retinopathy. The purpose of this study was to determine the roles played by superoxides formed by photoreceptors under hyperglycemic conditions on autophagy. To accomplish this, we cultured 661 W cells, a transformed murine cone cell line, with 5.5 or 25 mM glucose in the presence or absence of 3 methyl adenine (3MA) or rapamycin. The superoxides were determined by flow cytometry using hydroethidine as a fluorescence probe. The autophagy activity was determined by changes in the expression of LC3B2 and P62 by immunoblotting. The degree of mitophagy was determined by the accumulation of mitochondria and lysosomes. Apoptotic changes of 661 W cells were determined by the caspase 3/7 activities. Our results showed higher levels of P62 and superoxides in cells cultured in 25 mM glucose than in 5.5 mM glucose. Addition of 3MA caused a significant increase of P62, superoxides, and caspase 3/7 activities in the 661 W cells cultured in high glucose but not in low glucose. These findings suggest that autophagy is important for the functioning and survival of 661 W cells under hyperglycemic conditions. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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14 pages, 2815 KiB

Open AccessArticle

RORγt Inhibitor-SR1001 Halts Retinal Inflammation, Capillary Degeneration, and the Progression of Diabetic Retinopathy

by Thomas E. Zapadka, Sarah I. Lindstrom, Brooklyn E. Taylor, Chieh A. Lee, Jie Tang, Zakary R. R. Taylor, Scott J. Howell and Patricia R. Taylor

Int. J. Mol. Sci. 2020, 21(10), 3547; https://doi.org/10.3390/ijms21103547 - 17 May 2020

Cited by 19 | Viewed by 3437

Abstract

Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic [...] Read more.

Diabetic retinopathy is a diabetes-mediated retinal microvascular disease that is the leading cause of blindness in the working-age population worldwide. Interleukin (IL)-17A is an inflammatory cytokine that has been previously shown to play a pivotal role in the promotion and progression of diabetic retinopathy. Retinoic acid-related orphan receptor gammaT (RORγt) is a ligand-dependent transcription factor that mediates IL-17A production. However, the role of RORγt in diabetes-mediated retinal inflammation and capillary degeneration, as well as its potential therapeutic attributes for diabetic retinopathy has not yet been determined. In the current study, we examined retinal inflammation and vascular pathology in streptozotocin-induced diabetic mice. We found RORγt expressing cells in the retinal vasculature of diabetic mice. Further, diabetes-mediated retinal inflammation, oxidative stress, and retinal endothelial cell death were all significantly lower in RORγt^−/− mice. Finally, when a RORγt small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for RORγt in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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15 pages, 7923 KiB

Open AccessArticle

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid

by Soo Jin Kim, Sang A. Kim, Yeong A. Choi, Do Young Park and Junyeop Lee

Int. J. Mol. Sci. 2020, 21(6), 2158; https://doi.org/10.3390/ijms21062158 - 20 Mar 2020

Cited by 21 | Viewed by 5115

Abstract

Structural alterations of pericytes in microvessels are important features of diabetic retinopathy. Although capillary pericytes had been known not to have α-smooth muscle actin (αSMA), a recent study revealed that a specific fixation method enabled the visualization of αSMA along retinal capillaries. In [...] Read more.

Structural alterations of pericytes in microvessels are important features of diabetic retinopathy. Although capillary pericytes had been known not to have α-smooth muscle actin (αSMA), a recent study revealed that a specific fixation method enabled the visualization of αSMA along retinal capillaries. In this study, we applied snap-fixation in wild type and streptozotocin-induced diabetic mice to evaluate the differences in vascular smooth muscle cells of the retina and the choroid. Mice eyeballs were fixed in ice-cold methanol to prevent the depolymerization of filamentous actin. Snap-fixated retina showed αSMA expression in higher-order branches along the capillaries as well as the arterioles and venules, which were not detected by paraformaldehyde fixation. In contrast, most choriocapillaris, except those close to the arterioles, were not covered with αSMA-positive perivascular mural cells. Large choroidal vessels were covered with more αSMA-positive cells in the snap-fixated eyes. Diabetes induced less coverage of αSMA-positive perivascular mural cells overall, but they reached higher-order branches of the retinal capillaries, which was prominent in the aged mice. More αSMA-positive pericytes were observed in the choroid of diabetic mice, but the αSMA-positive expression reduced with aging. This study suggests the potential role of smooth muscle cells in the pathogenesis of age-related diabetic retinopathy and choroidopathy. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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19 pages, 4183 KiB

Open AccessArticle

Retinoprotection by BGP-15, a Hydroximic Acid Derivative, in a Type II Diabetic Rat Model Compared to Glibenclamide, Metformin, and Pioglitazone

by Zita Wachal, Mariann Bombicz, Dániel Priksz, Csaba Hegedűs, Diána Kovács, Adrienn Mónika Szabó, Rita Kiss, József Németh, Béla Juhász, Zoltán Szilvássy and Balázs Varga

Int. J. Mol. Sci. 2020, 21(6), 2124; https://doi.org/10.3390/ijms21062124 - 19 Mar 2020

Cited by 9 | Viewed by 3745

Abstract

High blood glucose and the consequential ischemia-reperfusion (I/R) injury damage vessels of the retina, deteriorating its function, which can be clearly visualized by electroretinography (ERG). The aim of the present study was to evaluate the possible retinoprotective effects of systemic BGP-15, an emerging [...] Read more.

High blood glucose and the consequential ischemia-reperfusion (I/R) injury damage vessels of the retina, deteriorating its function, which can be clearly visualized by electroretinography (ERG). The aim of the present study was to evaluate the possible retinoprotective effects of systemic BGP-15, an emerging drug candidate, in an insulin resistant animal model, the Goto-Kakizaki rat, and compare these results with well-known anti-diabetics such as glibenclamide, metformin, and pioglitazone, which even led to some novel conclusions about these well-known agents. Experiments were carried out on diseased animal model (Goto-Kakizaki rats). The used methods include weight measurement, glucose-related measurements—like fasting blood sugar analysis, oral glucose tolerance test, hyperinsulinemic euglycemic glucose clamp (HEGC), and calculations of different indices from HEGC results—electroretinography and Western Blot. Beside its apparent insulin sensitization, BGP-15 was also able to counteract the retina-damaging effect of Type II diabetes comparable to the aforementioned anti-diabetics. The mechanism of retinoprotective action may include sirtuin 1 (SIRT1) and matrix metalloproteinase 9 (MMP9) enzymes, as BGP-15 was able to elevate SIRT1 and decrease MMP9 expression in the eye. Based on our results, this emerging hydroximic acid derivative might be a future target of pharmacological developments as a potential drug against the harmful consequences of diabetes, such as diabetic retinopathy. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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19 pages, 3578 KiB

Open AccessArticle

Kynurenic Acid Protects Against Ischemia/Reperfusion-Induced Retinal Ganglion Cell Death in Mice

by Rooban B. Nahomi, Mi-Hyun Nam, Johanna Rankenberg, Stefan Rakete, Julie A. Houck, Ginger C. Johnson, Dorota L. Stankowska, Mina B. Pantcheva, Paul S. MacLean and Ram H. Nagaraj

Int. J. Mol. Sci. 2020, 21(5), 1795; https://doi.org/10.3390/ijms21051795 - 5 Mar 2020

Cited by 14 | Viewed by 4270

Abstract

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected [...] Read more.

Background: Glaucoma is an optic neuropathy and involves the progressive degeneration of retinal ganglion cells (RGCs), which leads to blindness in patients. We investigated the role of the neuroprotective kynurenic acid (KYNA) in RGC death against retinal ischemia/reperfusion (I/R) injury. Methods: We injected KYNA intravenously or intravitreally to mice. We generated a knockout mouse strain of kynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway that produces neurotoxic 3-hydroxykynurenine. To test the effect of mild hyperglycemia on RGC protection, we used streptozotocin (STZ) induced diabetic mice. Retinal I/R injury was induced by increasing intraocular pressure for 60 min followed by reperfusion and RGC numbers were counted in the retinal flat mounts. Results: Intravenous or intravitreal administration of KYNA protected RGCs against I/R injury. The I/R injury caused a greater loss of RGCs in wild type than in KMO knockout mice. KMO knockout mice had mildly higher levels of fasting blood glucose than wild type mice. Diabetic mice showed significantly lower loss of RGCs when compared with non-diabetic mice subjected to I/R injury. Conclusion: Together, our study suggests that the absence of KMO protects RGCs against I/R injury, through mechanisms that likely involve higher levels of KYNA and glucose. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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15 pages, 1560 KiB

Open AccessArticle

Homocysteine Disrupts Balance between MMP-9 and Its Tissue Inhibitor in Diabetic Retinopathy: The Role of DNA Methylation

by Ghulam Mohammad and Renu A. Kowluru

Int. J. Mol. Sci. 2020, 21(5), 1771; https://doi.org/10.3390/ijms21051771 - 5 Mar 2020

Cited by 31 | Viewed by 4659

Abstract

High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is [...] Read more.

High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is implicated in increased oxidative stress and activation of MMP-9, and in diabetic retinopathy, the activation of MMP-9 facilitates capillary cell apoptosis. Our aim was to investigate the mechanism by which homocysteine activates MMP-9 in diabetic retinopathy. Human retinal endothelial cells, incubated with/without 100 μM homocysteine, were analyzed for MMP-9 and its tissue inhibitor Timp1 expressions and interactions, and ROS levels. Timp1 and MMP-9 promoters were analyzed for methylated and hydroxymethylated cytosine levels (5mC and 5hmC respectively) by the DNA capture method, and DNA- methylating (Dnmt1) and hydroxymethylating enzymes (Tet2) binding by chromatin immunoprecipitation. The results were confirmed in retinal microvessels from diabetic rats receiving homocysteine. Homocysteine supplementation exacerbated hyperglycaemia-induced MMP-9 and ROS levels and decreased Timp1 and its interactions with MMP-9. Homocysteine also aggravated Dnmts and Tets activation, increased 5mC at Timp1 promoter and 5hmC at MMP-9 promoter, and suppressed Timp1 transcription and activated MMP-9 transcription. Similar results were obtained from retinal microvessels from diabetic rats receiving homocysteine. Thus, hyperhomocysteinemia in diabetes activates MMP-9 functionally by reducing Timp1-MMP-9 interactions and transcriptionally by altering DNA methylation-hydroxymethylation of its promoter. The regulation of homocysteine could prevent/slow down the development of retinopathy and prevent their vision loss in diabetic patients. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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16 pages, 3109 KiB

Open AccessArticle

Extracellular Vesicle-Induced Classical Complement Activation Leads to Retinal Endothelial Cell Damage via MAC Deposition

by Chao Huang, Kiera P. Fisher, Sandra S. Hammer and Julia V. Busik

Int. J. Mol. Sci. 2020, 21(5), 1693; https://doi.org/10.3390/ijms21051693 - 1 Mar 2020

Cited by 22 | Viewed by 5152

Abstract

Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in [...] Read more.

Several studies have suggested that there is a link between membrane attack complex (MAC) deposition in the retina and the progression of diabetic retinopathy (DR). Our recent investigation demonstrated that circulating IgG-laden extracellular vesicles contribute to an increase in retinal vascular permeability in DR through activation of the complement system. However, the mechanism through which extracellular vesicle-induced complement activation contributes to retinal vascular cytolytic damage in DR is not well understood. In this study, we demonstrate that IgG-laden extracellular vesicles in rat plasma activate the classical complement pathway, and in vitro Streptozotocin (STZ)-induced rat diabetic plasma results in MAC deposition and cytolytic damage in human retinal endothelial cells (HRECs). Moreover, removal of the plasma extracellular vesicles reduced the MAC deposition and abrogated cytolytic damage seen in HRECs. Together, the results of this study demonstrate that complement activation by IgG-laden extracellular vesicles in plasma could lead to MAC deposition and contribute to endothelium damage and progression of DR. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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13 pages, 2126 KiB

Open AccessArticle

Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models

by Yohei Tomita, Zhongjie Fu, Zhongxiao Wang, Bertan Cakir, Steve S. Cho, William Britton, Ye Sun, Ann Hellström, Saswata Talukdar and Lois E.H. Smith

Int. J. Mol. Sci. 2020, 21(4), 1188; https://doi.org/10.3390/ijms21041188 - 11 Feb 2020

Cited by 22 | Viewed by 4243

Abstract

The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice [...] Read more.

The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21- or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicle- treated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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11 pages, 2308 KiB

Open AccessArticle

Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

by Yohei Tomita, Nobuhiro Ozawa, Yukihiro Miwa, Ayako Ishida, Masayuki Ohta, Kazuo Tsubota and Toshihide Kurihara

Int. J. Mol. Sci. 2019, 20(23), 5878; https://doi.org/10.3390/ijms20235878 - 23 Nov 2019

Cited by 37 | Viewed by 7182

Abstract

Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of [...] Read more.

Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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Review

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22 pages, 2755 KiB

Open AccessReview

Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

by Brahim Chaqour and Charles Karrasch

Int. J. Mol. Sci. 2020, 21(10), 3487; https://doi.org/10.3390/ijms21103487 - 15 May 2020

Cited by 18 | Viewed by 6186

Abstract

The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or [...] Read more.

The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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20 pages, 2259 KiB

Open AccessReview

Leveraging Nuclear Receptors as Targets for Pathological Ocular Vascular Diseases

by Pei-Li Yao, Jeremy Peavey and Goldis Malek

Int. J. Mol. Sci. 2020, 21(8), 2889; https://doi.org/10.3390/ijms21082889 - 21 Apr 2020

Cited by 7 | Viewed by 3098

Abstract

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. [...] Read more.

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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22 pages, 3476 KiB

Open AccessReview

Genotypes and Phenotypes: A Search for Influential Genes in Diabetic Retinopathy

by Andrea P. Cabrera, Rushi N. Mankad, Lauren Marek, Ryan Das, Sampath Rangasamy, Finny Monickaraj and Arup Das

Int. J. Mol. Sci. 2020, 21(8), 2712; https://doi.org/10.3390/ijms21082712 - 14 Apr 2020

Cited by 20 | Viewed by 5871

Abstract

Although gene–environment interactions are known to play an important role in the inheritance of complex traits, it is still unknown how a genotype and the environmental factors result in an observable phenotype. Understanding this complex interaction in the pathogenesis of diabetic retinopathy (DR) [...] Read more.

Although gene–environment interactions are known to play an important role in the inheritance of complex traits, it is still unknown how a genotype and the environmental factors result in an observable phenotype. Understanding this complex interaction in the pathogenesis of diabetic retinopathy (DR) remains a big challenge as DR appears to be a disease with heterogenous phenotypes with multifactorial influence. In this review, we examine the natural history and risk factors related to DR, emphasizing distinct clinical phenotypes and their natural course in retinopathy. Although there is strong evidence that duration of diabetes and metabolic factors play a key role in the pathogenesis of DR, accumulating new clinical studies reveal that this disease can develop independently of duration of diabetes and metabolic dysfunction. More recently, studies have emphasized the role of genetic factors in DR. However, linkage analyses, candidate gene studies, and genome-wide association studies (GWAS) have not produced any statistically significant results. Our recently initiated genomics study, the Diabetic Retinopathy Genomics (DRGen) Study, aims to examine the contribution of rare and common variants in the development DR, and how they can contribute to clinical phenotype, rate of progression, and response to available therapies. Our preliminary findings reveal a novel set of genetic variants associated with proangiogenic and inflammatory pathways that may contribute to DR pathogenesis. Further investigation of these variants is necessary and may lead to development of novel biomarkers and new therapeutic targets in DR. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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21 pages, 1445 KiB

Open AccessReview

MicroRNAs in Vascular Eye Diseases

by Chi-Hsiu Liu, Shuo Huang, William R. Britton and Jing Chen

Int. J. Mol. Sci. 2020, 21(2), 649; https://doi.org/10.3390/ijms21020649 - 19 Jan 2020

Cited by 41 | Viewed by 5808

Abstract

Since the discovery of the first microRNA (miRNA) decades ago, studies of miRNA biology have expanded in many biomedical research fields, including eye research. The critical roles of miRNAs in normal development and diseases have made miRNAs useful biomarkers or molecular targets for [...] Read more.

Since the discovery of the first microRNA (miRNA) decades ago, studies of miRNA biology have expanded in many biomedical research fields, including eye research. The critical roles of miRNAs in normal development and diseases have made miRNAs useful biomarkers or molecular targets for potential therapeutics. In the eye, ocular neovascularization (NV) is a leading cause of blindness in multiple vascular eye diseases. Current anti-angiogenic therapies, such as anti-vascular endothelial growth factor (VEGF) treatment, have their limitations, indicating the need for investigating new targets. Recent studies established the roles of various miRNAs in the regulation of pathological ocular NV, suggesting miRNAs as both biomarkers and therapeutic targets in vascular eye diseases. This review summarizes the biogenesis of miRNAs, and their functions in the normal development and diseases of the eye, with a focus on clinical and experimental retinopathies in both human and animal models. Discovery of novel targets involving miRNAs in vascular eye diseases will provide insights for developing new treatments to counter ocular NV. Full article

(This article belongs to the Special Issue The Diabetic Eye Disease: Mechanisms Underlying Pathophysiology and Therapies)

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