Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

He, Jianbo; Wang, Hong; Liu, Ying; Li, Wen; Kim, Dorothy; Hu, Huang

doi:10.1155/2015/605946

Cited by 42 publications

(29 citation statements)

References 37 publications

(43 reference statements)

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“…In diabetic mice receiving control, VE-cadherin was found to be discontinuous or diffuse at the junctions of deep retinal capillaries (Fig. 3g) compared with non-diabetic animals, consistent with previous reports [5,18]. In contrast, CD5-2-treated diabetic mice displayed continuous VEcadherin expression at the junctions of microvessels in the deep plexus, with the level of VE-cadherin expression similar to that seen in non-diabetic animals (Fig.…”

Section: Cd5-2 Increases Ve-cadherin Expressionsupporting

confidence: 90%

“…A marked reduction in levels of VE-cadherin is seen in human retina obtained post-mortem from individuals with diabetes [15], while increased plasma levels have been observed in individuals with type 2 diabetes, suggesting that it is shed from the endothelium [16]. Higher levels of phosphorylation and degradation of VE-cadherin have been observed with increased vascular leakage in diabetic rodents [5,17,18]. Thus, a drug that restores the levels of VE-cadherin may have profound effects on the pathology of diabetic retinopathy, limiting vascular leakage and inhibiting angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

et al. 2018

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Aims/hypothesis A major feature of diabetic retinopathy is breakdown of the blood-retinal barrier, resulting in macular oedema. We have developed a novel oligonucleotide-based drug, CD5-2, that specifically increases expression of the key junctional protein involved in barrier integrity in endothelial cells, vascular-endothelial-specific cadherin (VE-cadherin). CD5-2 prevents the mRNA silencing by the pro-angiogenic microRNA, miR-27a. CD5-2 was evaluated in animal models of ocular neovascularisation and vascular leak to determine its potential efficacy for diabetic retinopathy.Methods CD5-2 was tested in three mouse models of retinal dysfunction: conditional Müller cell depletion, streptozotocininduced diabetes and oxygen-induced retinopathy. Vascular permeability in the Müller cell-knockout model was assessed by fluorescein angiography. The Evans Blue leakage method was used to determine vascular permeability in streptozotocin-and oxygen-induced retinopathy models. The effects of CD5-2 on retinal neovascularisation, inter-endothelial junctions and pericyte coverage in streptozotocin-and oxygen-induced retinopathy models were determined by staining for isolectin-B4, VE-cadherin and neural/glial antigen 2 (NG2). Blockmir CD5-2 localisation in diseased retina was determined using fluorescent in situ hybridisation. The effects of CD5-2 on VE-cadherin expression and in diabetic retinopathy-associated pathways, such as the transforming growth factor beta (TGF-β) and wingless/integrated (WNT) pathway, were confirmed using western blot of lysates from HUVECs, a mouse brain endothelial cell line and a VE-cadherin null mouse endothelial cell line. Results CD5-2 penetrated the vasculature of the eye in the oxygen-induced retinopathy model. Treatment of diseased mice with CD5-2 resulted in reduced vascular leak in all three animal models, enhanced expression of VE-cadherin in the microvessels of the eye and improved pericyte coverage of the retinal vasculature in streptozotocin-induced diabetic models and oxygen-induced retinopathy models. Further, CD5-2 reduced the activation of retinal microglial cells in the streptozotocin-induced diabetic model. The positive effects of CD5-2 seen in vivo were further confirmed in vitro by increased protein expression of VEcadherin, SMAD2/3 activity, and platelet-derived growth factor B (PDGF-B). Conclusions/interpretation CD5-2 has therapeutic potential for individuals with vascular-leak-associated retinal diseases based on its ease of delivery and its ability to reverse vascular dysfunction and inflammatory aspects in three animal models of retinopathy.

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Section: Cd5-2 Increases Ve-cadherin Expressionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

et al. 2018

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“…Additionally, the blockade of VEGFR1 suppressed vascular leakage and disorganization of ZO-1 (He et al, 2015). As we found the regulatory role of miR-15a/16 on the levels of TGF-beta3, VEGF, and tight junction proteins, we examined the effects of miR-15a/16 on the permeability of endothelial cells in vitro (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It was shown that TGF-beta signaling mediated an increase in VEGF in ARPE-19 cells under hyperglycemic conditions (Grigsby, Betts, Vidro-Kotchan, Culbert, & Tsin, 2012). Increased levels of VEGF signaling have also been shown in diabetic retina (Witmer et al, 2002) and the blockade of VEGFR1 suppressed retinal leukostasis, vascular leakage, and disorganization of zonula occludens-1 (ZO-1) (He et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Liu

Steinle

2017

Vision Research

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Hyperglycemia is a significant risk factor for diabetic retinopathy and induces multiple biochemical changes, including inflammation and endothelial dysfunction in the retina. Alterations in microRNA expression have been implicated in the pathological responses of diabetic retinopathy and the manipulation of microRNA may provide powerful strategy for therapeutics. Among the predicted targets of miR-15a and -16 are TGF-beta3, SMAD2/3, and VEGF, all of which are known to play a role in vascular endothelial functions. The purpose of this study was to investigate the hypothesis that miR-15a/16 inhibits TGF-beta3/VEGF signaling to maintain retinal endothelial cell barrier protein levels. Human primary retinal endothelial cells (REC) were maintained in normal (5 mM) glucose or transferred to high glucose medium (25 mM) for 3 days. REC were transfected with miRNA mimics (hsa-miR-15a-5p and -16-5p). Retinal lysates from miR-15a-transgenic mice were also analyzed. We demonstrated that overexpression of miR-15a/16 resulted in decreased TGF-beta3 signaling and VEGF levels in cultured REC grown in high glucose conditions. In addition, the levels of tight junction proteins, zonula occludens-1 (ZO-1) and occludin, were elevated in REC following overexpression of miR-15a and -16. Overexpression of miR-15a and - 16 played a role in reducing cellular permeability through inhibition of VEGF signaling in REC cultured under high glucose conditions. Using miR-15a-transgenic mice, we demonstrated the regulatory role of miR-15a on TGF-beta3 signaling and tight junction proteins in vivo. Our outcomes suggest that miR-15a/16 maintain the retinal endothelial cell barrier by reducing TGFbeta3/VEGF signaling and increasing levels of key tight junction proteins.

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“…24,[56][57][58] In this study, the mouse STZ model was selected, since this is the most common diabetic mouse model described in literature. 24 Different research groups have used this model to assess vascular leakage, 43,[59][60][61][62] and although several studies indeed delineated leakage in the diabetic mouse retina, the Müller glia reactivity was also studied via histologic staining for vimentin retinal staining and showed significantly more IPL/INL crossing fibers during early (1.7-fold increase) and during midterm diabetes (2.7-fold increase). (F) Gliosis was also diminished with 61% and 48% for aflibercept and TAAC, respectively.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

Sergeys

Étienne

Hove

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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The goal of this study was to perform an extensive temporal characterization of the early pathologic processes in the streptozotocin (STZ)-induced diabetic retinopathy (DR) mouse model, beyond the vascular phenotype, and to investigate the potential of clinically relevant compounds in attenuating these processes. METHODS. Visual acuity and contrast sensitivity (CS) were studied in the mouse STZ model until 24 weeks postdiabetes onset. ERG, spectral domain optical coherence tomography (SD-OCT), leukostasis, and immunohistochemistry were applied to investigate neurodegeneration, inflammation, and gliosis during early-, mid-and late-phase diabetes. Aflibercept or triamcinolone acetonide (TAAC) was administered to investigate their efficacy on the aforementioned processes. RESULTS. Visual acuity and CS loss started at 4 and 18 weeks postdiabetes onset, respectively, and progressively declined over time. ERG amplitudes were diminished and OP latencies increased after 6 weeks, whereas SD-OCT revealed retinal thinning from 4 weeks postdiabetes. Immunohistochemical analyses linked these findings to retinal ganglion and cholinergic amacrine cell loss at 4 and 8 weeks postdiabetes onset, respectively, which was further decreased after aflibercept administration. The number of adherent leukocytes was augmented after 2 weeks, whereas increased micro-and macroglia reactivity was present from 4 weeks postdiabetes. Aflibercept or TAAC showed improved efficacy on inflammation and gliosis. CONCLUSIONS. STZ-induced diabetic mice developed early pathologic DR hallmarks, from which inflammation seemed the initial trigger, leading to further development of functional and morphologic retinal changes. These findings indicate that the mouse STZ model is suitable to study novel integrative non-vascular therapies to treat early DR.

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Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

Cited by 42 publications

References 37 publications

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

miR-15a/16 inhibits TGF-beta3/VEGF signaling and increases retinal endothelial cell barrier proteins

Longitudinal In Vivo Characterization of the Streptozotocin-Induced Diabetic Mouse Model: Focus on Early Inner Retinal Responses

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