scholarly journals MEF2C Ablation in Endothelial Cells Reduces Retinal Vessel Loss and Suppresses Pathologic Retinal Neovascularization in Oxygen-Induced Retinopathy

2012 ◽  
Vol 180 (6) ◽  
pp. 2548-2560 ◽  
Author(s):  
Zhenhua Xu ◽  
Junsong Gong ◽  
Debasish Maiti ◽  
Linh Vong ◽  
Lijuan Wu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Retinal Vessel ◽  
Retinal Neovascularization ◽  
Oxygen Induced Retinopathy

Hypoxia-Induced Annexin A2 Expression Regulates Oxygen-Induced Retinopathy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 471-471
Author(s):  
Bihui Huang ◽  
Arun B Deora ◽  
Guangzhi Sui ◽  
Katherine A. Hajjar
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Fold Increase ◽  
Annexin A2 ◽  
Retinal Neovascularization ◽  
Immunofluorescent Staining ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Fibrin Deposition ◽  
Oxygen Induced Retinopathy

Abstract Abstract 471 Annexin A2 (A2), a Ca2+-dependent membrane binding protein that usually complexes with a S100 protein, p11, regulates fibrinolysis by serving as an endothelial cell co-receptor for plasminogen and tissue plasminogen activator to promote plasmin generation. Compared to A2+/+ mice, A2-/- mice have reduced post-hyperoxic retinal neovascularization in the model of oxygen-induced retinopathy (OIR) that mimics human retinopathy of prematurity. Here, we sought to determine the mechanism by which A2 contributes to the pathogenesis of OIR. A2+/+ mouse pups (P7) were placed with their dams in a high O2 (75%) chamber for 5 consecutive days (until P12), and then rapidly shifted to room air (21% O2) for several more days. Mouse retinas were isolated over a range of time points for analysis of neovascularization, A2 protein and mRNA expression, fibrin deposition, cell proliferation and apoptosis assays. In post-hyperoxic A2+/+ mice, we noted extensive retinal neovascularization along with a more than 10-fold increase of VEGFA compared to retinas of mice maintained in room air. Both A2 protein and mRNA levels increased 2-4-fold in mouse retinas with OIR in comparison with expression of either CD31 or VE-cadherin 5. p11 and hypoxia-inducible factor-1α (HIF-1α) protein, but not mRNA levels, also increased 2-4-fold during OIR. Because increased A2 expression was predominantly associated with retinal neovessels, we examined the response of cultured endothelial cells to hypoxia, and observed a 2-4-fold increase in A2 protein and mRNA. Although HIF-1α stabilization was not affected by A2 deficiency, upregulation of A2 by hypoxia was HIF-1α dependent. Expression of A6, on the other hand, was not upregulated by hypoxia. Neither erythropoietin (EPO) nor VEGFA signaling changed A2 expression. In addition, hypoxic endothelial cells translocated 50% more A2 protein to the cell surface, generated 30% more plasmin, and migrated twice as efficiently. While stability of A2 mRNA was not changed by hypoxia-related stimuli, we observed direct binding between HIF-1α and the A2 promoter by electrophoretic mobility shift assay, and a 3-4-fold increased A2 promoter activity in the presence of HIF-1α and HIF-1β by luciferase reporter assay. Promoter activation was abrogated when the HIF-1α binding site within the A2 promoter was mutated. By immunofluorescent staining of post-hyperoxic P17 retinal sections, we found that infiltration of endothelial cells and pericytes was 2-fold greater in A2+/+ mice as compared to A2-/- mice. In addition, there was significantly less fibrin deposition, more macrophage recruitment, less apoptosis and greater cell proliferation in P17 post-hyperoxic retinas of A2+/+ mice as compared to A2-/- mice. In conclusion, annexin A2 is upregulated by hypoxia through direct HIF-1α-mediated transcriptional regulation. Upregulated A2 appears to enhance plasmin generation, facilitate directed migration of vascular endothelial cells, and enable the recruitment of supporting cells (e.g. pericytes) and inflammatory cells (e.g. macrophages). It also reduces fibrin deposition, inhibits apoptosis, and promotes cell proliferation, thereby promoting pathologic oxygen-induced retinal neovascularization. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Aster koraiensis Extract and Chlorogenic Acid Inhibit Retinal Angiogenesis in a Mouse Model of Oxygen-Induced Retinopathy

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Junghyun Kim ◽  
Yun Mi Lee ◽  
Wookwon Jung ◽  
Su-Bin Park ◽  
Chan-Sik Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Mouse Model ◽  
Chlorogenic Acid ◽  
Vascular Endothelial Cells ◽  
Tube Formation ◽  
Retinal Neovascularization ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Oxygen Induced Retinopathy

Aster koraiensis extract (AKE) is a standard dietary herbal supplement. Chlorogenic acid (CA) is the major compound present in AKE. Retinal neovascularization is a common pathophysiology of retinopathy of prematurity, diabetic retinopathy, and wet form age-related macular degeneration. In this study, we aimed to evaluate the effects of AKE and CA on retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Vascular endothelial growth factor- (VEGF-) induced tube formation was assayed in human vascular endothelial cells. Experimental retinal neovascularization was induced by exposing C57BL/6 mice to 75% oxygen on postnatal day 7 (P7) and then returning them to normal oxygen pressure on P12. AKE (25 and 50 mg/kg/day) and CA (25 and 50 mg/kg/day) were administered intraperitoneally for 5 days (P12–P16). Retinal flat mounts were prepared to measure the extent of retinal neovascularization at P17. The incubation of human vascular endothelial cells with AKE and CA (1–10 μg/mL) resulted in the inhibition of VEGF-mediated tube formation in a dose-dependent manner. The neovascular area was significantly smaller in AKE or CA-treated mice than in the vehicle-treated mice. These results suggest that AKE is a potent antiangiogenic agent and that its antiangiogenic activity may, in part, be attributable to the bioactive component CA.

scholarly journals NADPH Oxidase 4-Derived H2O2Promotes Aberrant Retinal Neovascularization via Activation of VEGF Receptor 2 Pathway in Oxygen-Induced Retinopathy

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Jingming Li ◽  
Joshua J. Wang ◽  
Sarah X. Zhang
Keyword(s):  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Tube Formation ◽  
Retinal Neovascularization ◽  
Mouse Retina ◽  
Vegf Receptor ◽  
Retinal Endothelial Cells ◽  
Oxygen Induced Retinopathy ◽  
Nadph Oxidase 4 ◽  
Promising Therapeutic Approach

NADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidase in retinal endothelial cells. Our previous study suggests that upregulation of Nox4 in retinal endothelial cells contributes to retinal vascular leakage in diabetes. In the current study, we investigated the role and mechanism of Nox4 in regulation of retinal neovascularization (NV), a hallmark of proliferative diabetic retinopathy (PDR), using a mouse model of oxygen-induced retinopathy (OIR). Our results confirmed that Nox4 was expressed predominantly in retinal vasculature of mouse retina. Retinal expression of Nox4 was markedly increased in OIR, in parallel with enhanced phosphorylation of ERK. In human retinal microvascular endothelial cells (HRECs), overexpression of Nox4 by adenovirus significantly increased extracellular H2O2generation, resulting in intensified VEGFR2 activation and exacerbated angiogenesis upon VEGF stimulation. In contrast, silencing Nox4 expression or scavenging H2O2by polyethylene glycol- (PEG-) conjugated catalase inhibited endothelial migration, tube formation, and VEGF-induced activation of VEGFR2 signaling. Importantly, knockdown of retinal Nox4 by adenovirus-delivered siRNA significantly reduced ERK activation and attenuated retinal NV formation in OIR. Taken together, our data indicate that Nox4 promotes retinal NV formation through H2O2/VEGFR2/ERK signaling pathway. Reducing retinal Nox4 expression may represent a promising therapeutic approach for neovascular retinal diseases such as PDR.

scholarly journals Role of thromboxane in retinal microvascular degeneration in oxygen-induced retinopathy

2001 ◽  
Vol 90 (6) ◽  
pp. 2279-2288 ◽  
Author(s):  
Martin H. Beauchamp ◽  
Ana Katherine Martinez-Bermudez ◽  
Fernand Gobeil ◽  
Anne Marilise Marrache ◽  
Xin Hou ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Endothelial Cell ◽  
Oxidant Stress ◽  
Microvascular Endothelial Cell ◽  
Oxygen Induced Retinopathy ◽  
Rat Pups ◽  
Endothelial Cell Death ◽  
Peroxidation Product ◽  
Synthase Inhibitor

Microvascular degeneration is an important event in oxygen-induced retinopathy (OIR), a model of retinopathy of prematurity. Because oxidant stress abundantly generates thromboxane A2(TxA2), we tested whether TxA2plays a role in retinal vasoobliteration of OIR and contributes to such vascular degeneration by direct endothelial cytotoxicity. Hyperoxia-induced retinal vasoobliteration in rat pups (80% O2exposure from postnatal days 5–14) was associated with increased TxB2generation and was significantly prevented by TxA2synthase inhibitor CGS-12970 (10 mg · kg−1· day−1) or TxA2-receptor antagonist CGS-22652 (10 mg · kg−1· day−1). TxA2mimetics U-46619 (EC5050 nM) and I-BOP (EC505 nM) caused a time- and concentration-dependent cell death of neuroretinovascular endothelial cells from rats as well as newborn pigs but not of smooth muscle and astroglial cells; other prostanoids did not cause cell death. The peroxidation product 8-iso-PGF2, which is generated in OIR, stimulated TxA2formation by endothelial cells and triggered cell death; these effects were markedly diminished by CGS-12970. TxA2-dependent neuroretinovascular endothelial cell death was mostly by necrosis and to a lesser extent by apoptosis. The data identify an important role for TxA2in vasoobliteration of OIR and unveil a so far unknown function for TxA2in directly triggering neuroretinal microvascular endothelial cell death. These effects of TxA2might participate in other ischemic neurovascular injuries.

scholarly journals A PEDF-Derived Peptide Inhibits Retinal Neovascularization and Blocks Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Richard Longeras ◽  
Krysten Farjo ◽  
Michael Ihnat ◽  
Jian-Xing Ma
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Pigment Epithelium ◽  
Retinal Neovascularization ◽  
Endothelial Progenitor ◽  
Amino Acid Peptide ◽  
Oxygen Induced Retinopathy ◽  
Pigment Epithelium Derived Factor ◽  
Circulating Endothelial Progenitor Cells

Proliferative diabetic retinopathy is characterized by pathological retinal neovascularization, mediated by both angiogenesis (involving mature endothelial cells) and vasculogenesis (involving bone marrow-derived circulating endothelial progenitor cells (EPCs)). Pigment epithelium-derived factor (PEDF) contains an N-terminal 34-amino acid peptide (PEDF-34) that has antiangiogenic properties. Herein, we present a novel finding that PEDF-34 also possesses antivasculogenic activity. In the oxygen-induced retinopathy (OIR) model using transgenic mice that have Tie2 promoter-driven GFP expression, we quantified Tie2GFP+cells in bone marrow and peripheral blood by fluorescence-activated cell sorting (FACS). OIR significantly increased the number of circulating Tie2-GFP+at P16, correlating with the peak progression of neovascularization. Daily intraperitoneal injections of PEDF-34 into OIR mice decreased the number of Tie2-GFP+cells in the circulation at P16 by 65% but did not affect the number of Tie2-GFP+cells in the bone marrow. These studies suggest that PEDF-34 attenuates EPC mobilization from the bone marrow into the blood circulation during retinal neovascularization.

scholarly journals Inhibitory effect of Samul-tang on retinal neovascularization in oxygen-induced retinopathy

2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Yun Mi Lee ◽  
Chan-Sik Kim ◽  
Kyuhyung Jo ◽  
Eun Jin Sohn ◽  
Jin Sook Kim ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Retinal Neovascularization ◽  
Oxygen Induced Retinopathy

scholarly journals Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1β/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ailing Sui ◽  
Xiuping Chen ◽  
Jikui Shen ◽  
Anna M. Demetriades ◽  
Yiyun Yao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Nlrp3 Inflammasome ◽  
Retinal Neovascularization ◽  
Platelet Derived Growth Factor ◽  
Vegf Receptor ◽  
Activation Pattern ◽  
Ischemic Retinopathy

Abstract Activation of the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome plays an important role in ocular neovascularization. In our study, we found that the expression and activation levels of NLRP3 inflammasome components, including NLRP3, an apoptosis-associated speck-like protein (ASC) containing caspase activation and recruitment domain (CARD) and caspase-1 (CAS1), were significantly upregulated. In addition, we found interleukin (IL)-1β activity increased while IL-18 activity decreased in the retinas of oxygen-induced ischemic retinopathy (OIR) mice. MCC950, an inhibitor of NLRP3, reversed the IL-1β/IL-18 activation pattern, inhibited the formation of retinal neovascularization (RNV), decreased the number of acellular capillaries and reduced leakage of retinal vessels. Moreover, MCC950 could regulate the expression of endothelial cell- and pericyte function-associated molecules, such as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1, VEGFR2, matrix metalloproteinase (MMP)2, MMP9, tissue inhibitor of metalloproteinases (TIMP)1, TIMP2, platelet-derived growth factor receptor-β (PDGFR-β), platelet-derived growth factor-B (PDGF-B), and angiopoietin2 (Ang2). In vitro, recombinant human (r)IL-18 and rIL-1β regulated the expression of endothelial cell- and pericyte function-associated molecules and the proliferation and migration of endothelial cells and pericytes. We therefore determined that inhibiting the NLRP3 inflammasome with MCC950 can regulate the function of endothelial cells and pericytes by reversing the IL-1β/IL-18 activation pattern to ameliorate RNV and leakage; thereby opening new avenues to treat RNV-associated ocular diseases.

Sign in / Sign up

Export Citation Format

Share Document