Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy

Behl, Tapan; Kotwani, Anita

doi:10.1016/j.phrs.2015.05.013

Cited by 140 publications

(108 citation statements)

References 56 publications

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“…nos. 4464066 and 4464084; Ambion; Thermo Fisher Scientific, Inc.) were transfected into 3x10 6 ECs and RPs for 48 h by electroporation, using a Nucleofector instrument (Lonza Cologne GmbH, Cologne, Germany) according to the manufacturer's protocol. For the IRS-1 interference experiment, HEK293 genomic DNA was used as the PCR template and the DNA fragment encoding mir-126 pre-miRNA (flanking upstream and downstream 30-50 nt) was amplified and inserted into the expressing vector pSilencer4.1CMV-puro (Ambion; Thermo Fisher Scientific, Inc.) as described previously (24).…”

Section: Methodsmentioning

confidence: 99%

“…IRS-1 is involved in the mediation of the metabolic and mitogenic effects of insulin in peripheral tissues, including skeletal muscle, liver and adipose tissue, by transmitting signals from the insulin receptor to downstream enzymes, which include PI3K, phosphoinositide-dependent kinase 1 and protein kinase B (Akt) (4). VEGF is an angiogenic factor is involved in the maintenance of vascular homeostasis (5) and in pathological angiogenesis in diabetic retinopathy (6). This regulation maybe clinically relevant, because intensive insulin treatment is associated with worsening of DR and is associated with VEGF expression levels.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1

Fang

Guo

et al. 2017

Oncology Letters

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Abstract. Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. IRS-1 was predicted to be the target gene of microRNA-126 (miR-126). The present study was designed to illustrate the involvement of miR-126 in the regulation of DR via targeting IRS-1. The present study revealed that the expression of miR-126 was significantly decreased while IRS-1 expression was increased in endothelial cells (ECs) and retinal pericytes (RPs) from a DR mouse model compared with healthy controls. Furthermore, a luciferase reporter assay confirmed the interaction between miR-126 and IRS-1. Following transfection with anmiR-126 mimic or miR-126 inhibitor, overexpression of miR-126 was demonstrated to suppress the invasion and viability of ECs and RPs and to inhibit the IRS-1 and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway protein expression levels, with inhibition of miR-126 leading to reverse results. Furthermore, transfection with small interfering RNA targeting IRS-1 altered the miR-126-induced effects observed in ECs, indicating that miR-126 may suppress angiogenesis in DR via inhibition ofIRS-1 expression. Taken together, the results of the present study suggested that miR-126 affected the expression of IRS-1, resulting in downregulated expression of PI3K/Akt pathway proteins, and also suppressed cell invasion and viability. These results may provide a potential therapeutic strategy for DR.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1

Fang

Guo

et al. 2017

Oncology Letters

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“…The vessel sprouting and maturation processes must be precisely regulated by balancing pro- and anti-angiogenic signals [4, 5]. The imbalanced signals due to excessive VEGF stimuli leads to overproduction of immature and defective vessels with chaotic organization as seen in pathological angiogenesis in tumors and diabetic retinopathy [6, 7]. In peripheral arterial disease, imbalanced angiogenesis appears to be a crucial reason for the failure of clinical trials for VEGF gene therapy that were conducted in attempts to reperfuse ischemic tissues with VEGF-induced new vessels [8–10].…”

Section: Introductionmentioning

confidence: 99%

R-Ras Inhibits VEGF-Induced p38MAPK Activation and HSP27 Phosphorylation in Endothelial Cells

Sawada

Komatsu³

2015

J Vasc Res

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R-Ras is a Ras family small GTPase that is highly expressed in mature functional blood vessels in normal tissues. It inhibits pathological angiogenesis and promotes vessel maturation and stabilization. Previous studies suggest that R-Ras affects cellular signaling in endothelial cells, pericytes and smooth-muscle cells to regulate vessel formation and remodeling in adult tissues. R-Ras suppresses VEGF-induced endothelial permeability and vessel sprouting while promoting normalization of pathologically developing vessels in mice. It attenuates VEGF receptor-2 (VEGFR2) activation by inhibiting internalization of the receptor upon VEGF ligand binding, leading to significant reduction of VEGFR2 autophosphorylation. Here, we show that R-Ras strongly suppresses the VEGF-dependent activation of stress-activated protein kinase-2/p38 mitogen-activated protein kinase (SAPK2/p38MAPK) and the phosphorylation of downstream heat-shock protein 27 (HSP27), a regulator of actin cytoskeleton organization, in endothelial cells. The suppression of p38MAPK activation and HSP27 phosphorylation by R-Ras concurred with altered actin cytoskeleton architecture, reduced membrane protrusion and inhibition of endothelial cell migration toward VEGF. Silencing of endogenous R-Ras by RNA interference increased membrane protrusion and cell migration stimulated by VEGF, and these effects were offset by p38MAPK inhibitor SB203580. These results suggest that R-Ras regulates angiogenic activities of endothelial cells in part via inhibition of the p38MAPK-HSP27 axis of VEGF signaling.

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“…The identification of the key role of this biomarker in diabetic retinopathy has led to the development of anti-VEGF treatments. There are several review articles regarding the role of VEGF and anti-VEGF agents in diabetic retinopathy [233][234][235]. Whilst VEGF genotype is linked with retinopathy risk [234], it is not yet used in clinical practice.…”

Section: Angiogenesis-related Biomarkersmentioning

confidence: 99%

Biomarkers in Diabetic Retinopathy

et al. 2015

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■ AbstractThere is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

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Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy

Cited by 140 publications

References 56 publications

MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1

MicroRNA-126 inhibits cell viability and invasion in a diabetic retinopathy model via targeting IRS-1

R-Ras Inhibits VEGF-Induced p38MAPK Activation and HSP27 Phosphorylation in Endothelial Cells

Biomarkers in Diabetic Retinopathy

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