scholarly journals Selective Targeting and Tissue Penetration to the Retina by a Systemically Administered Vascular Homing Peptide in Oxygen Induced Retinopathy (OIR)

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1932
Author(s):  
Maria Vähätupa ◽  
Niklas Salonen ◽  
Hannele Uusitalo-Järvinen ◽  
Tero A. H. Järvinen
Keyword(s):  
Retinal Diseases ◽  
Tissue Penetration ◽  
Retinal Tissue ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Selective Targeting ◽  
A Cell ◽  
Homing Peptide ◽  
Angiogenesis Model ◽  
Hypoxia Treatment

Pathological angiogenesis is the hallmark of ischemic retinal diseases among them retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Oxygen-induced retinopathy (OIR) is a pure hypoxia-driven angiogenesis model and a widely used model for ischemic retinopathies. We explored whether the vascular homing peptide CAR (CARSKNKDC) which recognizes angiogenic blood vessels can be used to target the retina in OIR. We were able to demonstrate that the systemically administered CAR vascular homing peptide homed selectively to the preretinal neovessels in OIR. As a cell and tissue-penetrating peptide, CAR also penetrated into the retina. Hyperoxia used to induce OIR in the retina also causes bronchopulmonary dysplasia in the lungs. We showed that the CAR peptide is not targeted to the lungs in normal mice but is targeted to the lungs after hyperoxia-/hypoxia-treatment of the animals. The site-specific delivery of the CAR peptide to the pathologic retinal vasculature and the penetration of the retinal tissue may offer new opportunities for treating retinopathies more selectively and with less side effects.

scholarly journals Imatinib Ameliorated Retinal Neovascularization by Suppressing PDGFR-α and PDGFR-β

2018 ◽  
Vol 48 (1) ◽  
pp. 263-273 ◽  
Author(s):  
Lingli Zhou ◽  
Xiaowei Sun ◽  
Zijing Huang ◽  
Tian Zhou ◽  
Xiaowei Zhu ◽  
...  
Keyword(s):  
Retinal Neovascularization ◽  
Imatinib Treatment ◽  
Retinal Diseases ◽  
Vascular Cells ◽  
Western Blots ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Angiogenic Effect ◽  
Systemic Side Effects ◽  
Isolectin B4

Background/Aims: Platelet-derived growth factors (PDGFs) have emerged as pivotal in pathological angiogenesis, which is a hallmark of various tumors and retinal diseases. Here we evaluated the anti-angiogenic effect of imatinib, an inhibitor of PDGF receptors α and β (PDGFR-α and -β), in retinal neovascularization using an oxygen-induced retinopathy (OIR) model. Methods: The OIR model was established and given imatinib or vehicle treatments daily from P12 to P16. At the peak of angiogenesis at P17, the neovascularization area was quantified on retinal whole-mounts with isolectin B4 staining. Immunofluorescence staining and western blots were used to determine the effect of imatinib on different vascular cells and the pathway molecules involved. Results: Imatinib effectively suppressed pathological angiogenesis in OIR mice and reduced the number of all three types of vascular cells, including endothelial cells, pericytes, and smooth muscle cells. Moreover, the expression and activation of PDGFR-α and -β were inhibited by imatinib. The imatinib-treated OIR mice presented with reduced expression of other potent pro-angiogenic factors such as VEGF and FGF2. No obvious retinal or systemic side effects were observed in the imatinib treatment group. Conclusions: Imatinib appears to be safe and effective in suppressing retinal neovascularization. Targeting PDGFs/PDGFRs may also be important for anti-angiogenic treatment and offer a viable alternative treatment for retinal angiogenic diseases.

scholarly journals Protein Kinase B (Akt) Promotes Pathological Angiogenesis in Murine Model of Oxygen-Induced Retinopathy

2011 ◽  
Vol 44 (2) ◽  
pp. 103-111 ◽  
Author(s):  
Peng Wang ◽  
Xiao-Feng Tian ◽  
Jun-Bo Rong ◽  
Dan Liu ◽  
Guo-Guo Yi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Murine Model ◽  
Protein Kinase B ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy

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

2019 ◽  
Vol 20 (23) ◽  
pp. 5878 ◽  
Author(s):  
Yohei Tomita ◽  
Nobuhiro Ozawa ◽  
Yukihiro Miwa ◽  
Ayako Ishida ◽  
Masayuki Ohta ◽  
...  
Keyword(s):  
Growth Factor ◽  
Large Scale ◽  
Luciferase Assay ◽  
Fibroblast Growth Factor 21 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy

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.

Application of Hydrogen in Ophthalmology

2020 ◽  
Vol 26 ◽  
Author(s):  
Hiroshi Takahashi
Keyword(s):  
Anterior Chamber ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Retinal Ischemia ◽  
Endothelial Damage ◽  
Retinal Diseases ◽  
Retinal Tissue ◽  
Cavitation Phenomenon ◽  
Irrigation Solution ◽  
Corneal Damage

: This report reviews studies on the use of H2 in the ophthalmological field. In retinal diseases, particularly in a retinal ischemia–reperfusion injury, effects of H2 are remarkable in reducing retinal tissue damage. H2 treatment of corneal damage caused by alkali or UVB suppressed scar formation. The most unique application of H2 in the ophthalmological field appears to be its use in phacoemulsification cataract surgery. Ultrasound oscillation produces ·OH through the cavitation phenomenon in the anterior chamber of the eye, which induces oxidative insults in the corneal endothelium. Phacoemulsification using H2 dissolved in the irrigation solution significantly suppressed the corneal endothelial damage. The effect of H2 was direct and clear, as H2 instantly scavenges ·OH produced by ultrasound oscillation in the anterior chamber, thereby suppressing oxidative insults during the phacoemulsification procedure.

scholarly journals A Magneto-Microfluidic System for Investigating the Influence of an Externally Induced Force Gradient in a Collagen Type I ECM on HMVEC Sprouting

2016 ◽  
Vol 22 (4) ◽  
pp. 413-424 ◽  
Author(s):  
Sahan C. B. Herath ◽  
Soheila Sharghi-Namini ◽  
Yue Du ◽  
Dongan Wang ◽  
Ruowen Ge ◽  
...  
Keyword(s):  
Magnetic Beads ◽  
Collagen Type ◽  
Collagen Type I ◽  
Microfluidic System ◽  
Collagen Fibers ◽  
Cell Behavior ◽  
Type I ◽  
Pathological Angiogenesis ◽  
A Cell

Advances in mechanobiology have suggested that physiological and pathological angiogenesis may be differentiated based on the ways in which the cells interact with the extracellular matrix (ECM) that exhibits partially different mechanical properties. This warrants investigating the regulation of ECM stiffness on cell behavior using angiogenesis assays. In this article, we report the application of the technique of active manipulation of ECM stiffness to study in vitro angiogenic sprouting of human microvascular endothelial cells (HMVECs) in a microfluidic device. Magnetic beads were embedded in the ECM through bioconjugation (between the streptavidin-coated beads and collagen fibers) in order to create a pretension in the ECM when under the influence of an external magnetic field. The advantage of using this magneto-microfluidic system is that the resulting change in the local deformability of the collagen fibers is only apparent to a cell at the pericellular level near the site of an embedded bead, while the global intrinsic material properties of the ECM remain unchanged. The results demonstrate that this system represents an effective tool for inducing noninvasively an external force on cells through the ECM, and suggest the possibility of creating desired stiffness gradients in the ECM for manipulating cell behavior in vitro.

scholarly journals Intraocular injection of KH902 alleviates retinal hypoxia in a mouse model of oxygen-induced retinopathy

2021 ◽  
pp. 38-38
Author(s):  
Ning Yang ◽  
Xuejun He ◽  
Ningzhi Zhang ◽  
Yiqiao Xing
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mouse Model ◽  
Vascular Endothelial ◽  
Ocular Diseases ◽  
Vegf Expression ◽  
Pathological Angiogenesis ◽  
Intraocular Injection ◽  
Oxygen Induced Retinopathy ◽  
Endothelial Growth Factor

Inhibition of vascular endothelial growth factor (VEGF) has been widely applied in antineovascularization therapies. As a novel anti-VEGF agent, KH902 (conbercept) is designed to restrain pathological angiogenesis. However, the effects of KH902 on retinal hypoxia have not been well studied. In a mouse model of oxygen-induced retinopathy (OIR), we assessed retinal hypoxia at postnatal days 14 (P14) and P17, as well as retinal neovascularization (RNV) at P17. In addition, we evaluated the protein level of VEGF and galectin-1 (Gal-1). Changes of the neuroretinal structure were also examined. Our results indicated that KH902 could remit retinal hypoxia in OIR at P14 and P17, which was an exciting novel finding for KH902 function. Additionally, we confirmed that KH902 markedly reduces RNV. Our results indicated that administration of KH902 downregulated VEGF expression, as well as Gal-1. Damage of neuroretinal structure after KH902 injection was not observed, which was also an encouraging result. Our study suggests that KH902 plays a role in alleviating retinal hypoxia and that it could be used for the treatment of other neovascular ocular diseases.

Long noncoding RNA MALAT1 participates in the pathological angiogenesis of diabetic retinopathy in an oxygen-induced retinopathy mouse model by sponging miR-203a-3p

2020 ◽  
Vol 98 (4) ◽  
pp. 219-227 ◽  
Author(s):  
Li Yu ◽  
Jinling Fu ◽  
Na Yu ◽  
Yazhen Wu ◽  
Ning Han
Keyword(s):  
Diabetic Retinopathy ◽  
Mouse Model ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Suppressive Effect ◽  
Tube Formation ◽  
Luciferase Reporter ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Dual Luciferase Reporter Assay

Diabetic retinopathy (DR) is a devastating complication of diabetes. The aim of the present study is to investigate the exact role and mechanism of long noncoding RNA MALAT1 (MALAT1) in the progress of DR. An oxygen-induced retinopathy (OIR) mouse model and high glucose (HG) stimulated human retinal microvascular endothelial cells (HRMECs) were employed to mimic the pathological statues of DR. Quantitative real-time PCR (qRT-PCR) and Western blot results showed that MALAT1, VEGFA, and HIF-1α levels were increased in DR retinal tissues and HG-stimulated HRMECs, whereas the expression of miR-203a-3p was decreased. Knockdown of MALAT1 or upregulation of miR-203a-3p both suppressed HG-induced proliferation, migration, and tube formation of HRMECs. A dual-luciferase reporter assay showed that miR-203a-3p could bind to the predicted seed regions of MALAT1 as evidenced by the reduced luciferase activity. Furthermore, enforced downregulation of miR-203a-3p abolished the suppressive effect of MALAT1 silencing on HRMEC cell migration and tube formation. In conclusion, these data demonstrated that MALAT1 may affect angiogenesis by sponging miR-203a-3p in DR, suggesting that MALAT1 may act as a novel therapeutic target for the treatment of DR.

scholarly journals Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling

2020 ◽  
Vol 6 (1) ◽  
pp. eaay3566 ◽  
Author(s):  
Hua Liu ◽  
Fang C. Mei ◽  
Wenli Yang ◽  
Hui Wang ◽  
Eitan Wong ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Specific Inhibitor ◽  
Aortic Ring ◽  
Notch Signaling Pathway ◽  
Growth Factor Signaling ◽  
Artery Ligation ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Carotid Artery Ligation ◽  
Genetic Deletion

In this study, we investigated the roles of Epac1 in pathological angiogenesis and its potential as a novel therapeutic target for the treatment of vasoproliferative diseases. Genetic deletion of Epac1 ameliorated pathological angiogenesis in mouse models of oxygen-induced retinopathy (OIR) and carotid artery ligation. Moreover, genetic deletion or pharmacological inhibition of Epac1 suppressed microvessel sprouting from ex vivo aortic ring explants. Mechanistic studies revealed that Epac1 acted as a previously unidentified inhibitor of the γ-secretase/Notch signaling pathway via interacting with γ-secretase and regulating its intracellular trafficking while enhancing vascular endothelial growth factor signaling to promote pathological angiogenesis. Pharmacological administration of an Epac-specific inhibitor suppressed OIR-induced neovascularization in wild-type mice, recapitulating the phenotype of genetic Epac1 knockout. Our results demonstrate that Epac1 signaling is critical for the progression of pathological angiogenesis but not for physiological angiogenesis and that the newly developed Epac-specific inhibitors are effective in combating proliferative retinopathy.

In situ calcium mapping in the mouse retina via time-of-flight secondary ion mass spectrometry: modulation of retinal angiogenesis by calcium ion in development and oxygen-induced retinopathy

2008 ◽  
Vol 86 (5) ◽  
pp. 459-467 ◽  
Author(s):  
Jeong Hun Kim ◽  
Jin Hyoung Kim ◽  
Young Suk Yu ◽  
Dong Hun Kim ◽  
Tae Geol Lee ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Calcium Ion ◽  
Secondary Ion Mass Spectrometry ◽  
Time Of Flight ◽  
Mouse Retina ◽  
Pathological Angiogenesis ◽  
Oxygen Induced Retinopathy ◽  
Tof Sims ◽  
Ion Mass Spectrometry ◽  
Secondary Ion

Pathological angiogenesis in the eye is the most common cause of blindness in all age groups. In physiological and pathological cellular processes including angiogenesis, ion homeostasis is greatly affected. This study is to investigate the role of calcium ion in physiological and pathological angiogenesis in the retina, which is based on the results of ion mapping by time-of-flight secondary ion mass spectrometry (TOF-SIMS). We provided that calcium distribution is the most accordant to change with physiological vessel formation of development in the retina and pathological angiogenesis of oxygen-induced retinopathy (OIR), which is supported by ion mapping in retinal tissue using TOF-SIMS. In addition to anti-proliferative and anti-angiogenic activity of the calcium inhibitor on endothelial cells, retinal neovascularization of OIR was effectively inhibited by the calcium inhibitor. Calcium ion could play a crucial role in physiological and pathological angiogenesis in the retina. Moreover, TOF-SIMS could be a good method to simultaneously evaluate the changes of variable ions of the retina in biological processes.

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