The Histone Deacetylase Inhibitor AN7, Attenuates Choroidal Neovascularization in a Mouse Model

: Choroidal neovascularization (CNV) is a complication of age-related macular degeneration and a major contributing factor to vision loss. In this paper, we show that in a mouse model of laser-induced CNV, systemic administration of Butyroyloxymethyl-diethyl phosphate (AN7), a histone deacetylase inhibitor (HDACi), significantly reduced CNV area and vascular leakage, as measured by choroidal flatmounts and fluorescein angiography. CNV area reduction by systemic AN7 treatment was similar to that achieved by intravitreal bevacizumab treatment. The expression of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF-2), and the endothelial cells marker CD31, was lower in the AN7 treated group in comparison to the control group at the laser lesion site. In vitro, AN7 facilitated retinal pigmented epithelium (RPE) cells tight junctions’ integrity during hypoxia, by protecting the hexagonal pattern of ZO-1 protein in the cell borders, hence reducing RPE permeability. In conclusion, systemic AN7 should be further investigated as a possible effective treatment for CNV.

Download Full-text

Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice

Journal of Clinical Medicine ◽

10.3390/jcm9072242 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2242

Author(s):

Ye Liu ◽

Kousuke Noda ◽

Miyuki Murata ◽

Di Wu ◽

Atsuhiro Kanda ◽

...

Keyword(s):

Growth Factor ◽

Choroidal Neovascularization ◽

Vision Loss ◽

Growth Factor Receptor ◽

Neutralizing Antibody ◽

Age Related Macular Degeneration ◽

Platelet Derived Growth Factor ◽

Growth Factor Signaling ◽

Age Related ◽

Subretinal Fibrosis

Neovascular age related macular degeneration (nAMD) leads to severe vision loss worldwide and is characterized by the formation of choroidal neovascularization (CNV) and fibrosis. In the current study, we aimed to investigate the effect of blockade for platelet derived growth factor receptor-β (PDGFR-β) on the formation of choroidal neovascularization and fibrosis in the laser-induced CNV model in mice. Firstly, the presence of PDGFR-β in CNV lesions were confirmed. Intravitreal injection of PDGFR-β neutralizing antibody significantly reduced the size of CNV and subretinal fibrosis. Additionally, subretinal hyperreflective material (SHRM), a landmark feature on OCT as a risk factor for subretinal fibrosis formation in nAMD patients was also suppressed by PDGFR-β blockade. Furthermore, pericytes were abundantly recruited to the CNV lesions during CNV formation, however, blockade of PDGFR-β significantly reduced pericyte recruitment. In addition, PDGF-BB stimulation increased the migration of the rat retinal pericyte cell line, R-rPCT1, which was abrogated by the neutralization of PDGFR-β. These results indicate that blockade of PDGFR-β attenuates laser-induced CNV and fibrosis through the inhibition of pericyte migration.

Download Full-text

Human Vascular Endothelial Growth Factor A165 Expression Induces the Mouse Model of Neovascular Age-Related Macular Degeneration

Genes ◽

10.3390/genes9090438 ◽

2018 ◽

Vol 9 (9) ◽

pp. 438 ◽

Cited By ~ 2

Author(s):

Emmi Kokki ◽

Tommi Karttunen ◽

Venla Olsson ◽

Kati Kinnunen ◽

Seppo Ylä-Herttuala

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Gene Transfer ◽

Mouse Model ◽

Choroidal Neovascularization ◽

Age Related Macular Degeneration ◽

Vascular Endothelial ◽

Time Points ◽

Age Related ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) expression induces age-related macular degeneration (AMD), which is a common vision-threatening disease due to choroidal neovascularization and a fibrovascular membrane. We describe a mouse model of neovascular AMD with the local expression of human VEGF-A165 in the eye. We use a transgenic mouse in which human VEGF-A165 has been silenced with the loxP-STOP fragment. The choroidal neovascularization and human VEGF-A165 expression in the mouse are induced by subretinal adenoviral Cre gene delivery. Cre gene transfer is compared with adenoviral LacZ gene transfer control. We characterize the AMD phenotype and changes in the vasculature by using fluorescein angiography, optical coherence tomography, and immunohistochemistry. At early time points, mice exhibit increases in retinal thickness (348 ± 114 µm vs. 231 ± 32 µm) and choroidal neovascularization area (12000 ± 15174 µm2 vs. 2169 ± 3495 µm2) compared with the control. At later time points, choroidal neovascularization develops into subretinal fibrovascular membrane. Human VEGF-A165 expression lasts several weeks. In conclusion, the retinas display vascular abnormalities consistent with choroidal neovascularization. Together with immunohistochemical findings, these changes resemble clinical AMD-like ocular pathologies. We conclude that this mouse model of Cre-induced choroidal neovascularization is useful for mimicking the pathogenesis of AMD, studying the effects of human VEGF-A165 in the retina, and evaluating anti-VEGF treatments for choroidal neovascularization.

Download Full-text

The Anti-Inflammatory Effect of Hydrogen Gas Inhalation and Its Influence on Laser-Induced Choroidal Neovascularization in a Mouse Model of Neovascular Age-Related Macular Degeneration

International Journal of Molecular Sciences ◽

10.3390/ijms222112049 ◽

2021 ◽

Vol 22 (21) ◽

pp. 12049

Author(s):

I-Chia Liang ◽

Wen-Chin Ko ◽

Yu-Jou Hsu ◽

Yi-Ru Lin ◽

Yun-Hsiang Chang ◽

...

Keyword(s):

Mouse Model ◽

Macular Degeneration ◽

Mrna Expression ◽

Choroidal Neovascularization ◽

Hydrogen Gas ◽

Age Related Macular Degeneration ◽

Fluorescence Angiography ◽

Control Group ◽

Necrosis Factor Alpha ◽

Age Related

Background: Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. Choroidal neovascularization (CNV) is the major pathologic feature of neovascular AMD. Oxidative damages and the ensuing chronic inflammation are representative of trigger events. Hydrogen gas (H2) has been demonstrated as an antioxidant and plays a role in the regulation of oxidative stress and inflammation. This experiment aimed to investigate the influence of H2 inhalation on a mouse model of CNV. Methods: Laser was used to induce CNV formation. C57BL/6J mice were divided into five groups: the control group; the laser-only group; and the 2 h, 5 h, and 2.5 h/2.5 h groups that received laser and H2 inhalation (21% oxygen, 42% hydrogen, and 37% nitrogen mixture) for 2 h, 5 h, and 2.5 h twice every day, respectively. Results: The severity of CNV leakage on fluorescence angiography showed a significant decrease in the H2 inhalation groups. The mRNA expression of hypoxia-inducible factor 1 alpha and its immediate downstream target vascular endothelial growth factor (VEGF) showed significant elevation after laser, and this elevation was suppressed in the H2 inhalation groups in an inhalation period length-related manner. The mRNA expression of cytokines, including tumor necrosis factor alpha and interlukin-6, also represented similar results. Conclusion: H2 inhalation could alleviate CNV leakage in a laser-induced mouse CNV model, and the potential mechanism might be related to the suppression of the inflammatory process and VEGF-driven CNV formation.

Download Full-text

Placental growth factor (PlGF) inhibition reduces choroidal neovascularization in a mouse model for age-related macular degeneration

Acta Ophthalmologica Scandinavica ◽

10.1111/j.1600-0420.2007.01063_3212.x ◽

2007 ◽

Vol 85 ◽

pp. 0-0

Author(s):

S VAN DE VEIRE ◽

G MOONS ◽

SA VINORES ◽

P CARMELIET ◽

I STALMANS

Keyword(s):

Growth Factor ◽

Mouse Model ◽

Macular Degeneration ◽

Choroidal Neovascularization ◽

Placental Growth Factor ◽

Age Related Macular Degeneration ◽

Age Related

Download Full-text

Cytochrome P450 monooxygenase lipid metabolites are significant second messengers in the resolution of choroidal neovascularization

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1620898114 ◽

2017 ◽

Vol 114 (36) ◽

pp. E7545-E7553 ◽

Cited By ~ 18

Author(s):

Eiichi Hasegawa ◽

Saori Inafuku ◽

Lama Mulki ◽

Yoko Okunuki ◽

Ryoji Yanai ◽

...

Keyword(s):

Cytochrome P450 ◽

Choroidal Neovascularization ◽

Vascular Function ◽

Vision Loss ◽

Second Messengers ◽

Age Related Macular Degeneration ◽

P450 Monooxygenase ◽

Genetic Ablation ◽

Age Related ◽

Lipid Metabolites

Age-related macular degeneration (AMD) is the most common cause of blindness for individuals age 50 and above in the developed world. Abnormal growth of choroidal blood vessels, or choroidal neovascularization (CNV), is a hallmark of the neovascular (wet) form of advanced AMD and leads to significant vision loss. A growing body of evidence supports a strong link between neovascular disease and inflammation. Metabolites of long-chain polyunsaturated fatty acids derived from the cytochrome P450 (CYP) monooxygenase pathway serve as vital second messengers that regulate a number of hormones and growth factors involved in inflammation and vascular function. Using transgenic mice with altered CYP lipid biosynthetic pathways in a mouse model of laser-induced CNV, we characterized the role of these lipid metabolites in regulating neovascular disease. We discovered that the CYP-derived lipid metabolites epoxydocosapentaenoic acids (EDPs) and epoxyeicosatetraenoic acids (EEQs) are vital in dampening CNV severity. Specifically, overexpression of the monooxygenase CYP2C8 or genetic ablation or inhibition of the soluble epoxide hydrolase (sEH) enzyme led to increased levels of EDP and EEQ with attenuated CNV development. In contrast, when we promoted the degradation of these CYP-derived metabolites by transgenic overexpression of sEH, the protective effect against CNV was lost. We found that these molecules work in part through their ability to regulate the expression of key leukocyte adhesion molecules, on both leukocytes and endothelial cells, thereby mediating leukocyte recruitment. These results suggest that CYP lipid signaling molecules and their regulators are potential therapeutic targets in neovascular diseases.

Download Full-text

The Effects of Indocyanine Green Dye-Enhanced Photocoagulation on the Blood Flow in the Choriocapillaris and the Choroidal Neovascularization (CNV)

10.1115/imece2000-2213 ◽

2000 ◽

Author(s):

C. von Kerczek ◽

L. Zhu ◽

A. Ernest ◽

C. Eggleton ◽

L. D. T. Topoleski ◽

...

Keyword(s):

Laser Treatment ◽

Choroidal Neovascularization ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The United States ◽

Age Related Macular Degeneration ◽

Central Vision ◽

Age Related ◽

Direct Laser

Abstract Age-related macular degeneration (AMD) is the most common cause of vision loss in patients aged 65 years and older in the United States. In the majority of cases, the loss of central vision is secondary to exudative changes and fibrovascular scarring following choroidal neovascularization (CNV). Prompt laser treatment is recommended [Asrani et al., 1996; Macular Photocoagulation Study Group, 1993; Schneider et al, 1998]. However, direct laser treatment to the entire subfoveal lesion is almost invariably associated with immediate loss of central vision. Loss of central vision may be due to direct damage to foveal photoreceptors and retinal pigment epithelium or from damage to the nerve fiber layer serving foveal function [Han et al., 1988].

Download Full-text

Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

Mediators of Inflammation ◽

10.1155/2010/546826 ◽

2010 ◽

Vol 2010 ◽

pp. 1-14 ◽

Cited By ~ 41

Author(s):

Claudio Campa ◽

Ciro Costagliola ◽

Carlo Incorvaia ◽

Carl Sheridan ◽

Francesco Semeraro ◽

...

Keyword(s):

Growth Factor ◽

Choroidal Neovascularization ◽

Inflammatory Mediators ◽

Transforming Growth Factor ◽

Pathological Condition ◽

Inflammatory Cells ◽

Angiogenic Factors ◽

Age Related Macular Degeneration ◽

Therapeutic Implications ◽

Age Related

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed.

Download Full-text