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

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.

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

2019 ◽  
Vol 20 (3) ◽  
pp. 714
Author(s):  
Mor Dahbash ◽  
Ruti Sella ◽  
Elinor Megiddo-Barnir ◽  
Yael Nisgav ◽  
Nataly Tarasenko ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mouse Model ◽  
Histone Deacetylase ◽  
Choroidal Neovascularization ◽  
Histone Deacetylase Inhibitor ◽  
Vision Loss ◽  
Age Related Macular Degeneration ◽  
Control Group ◽  
Age Related ◽  
Deacetylase Inhibitor

: 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.

Intravitreal Combined Aflibercept + Anti–Platelet-Derived Growth Factor Receptor β for Neovascular Age-Related Macular Degeneration

Ophthalmology ◽  
2020 ◽  
Vol 127 (2) ◽  
pp. 211-220 ◽  
Author(s):  
Jeffrey S. Heier ◽  
Charles C. Wykoff ◽  
Nadia K. Waheed ◽  
John W. Kitchens ◽  
Sunil S. Patel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Growth Factor Receptor ◽  
Age Related Macular Degeneration ◽  
Platelet Derived Growth Factor ◽  
Age Related

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

2017 ◽  
Vol 114 (36) ◽  
pp. E7545-E7553 ◽  
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.

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

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].

scholarly journals Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Karis Little ◽  
Maria Llorián-Salvador ◽  
Miao Tang ◽  
Xuan Du ◽  
Stephen Marry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Transforming Growth Factor ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Two Stage ◽  
Blocking Antibody ◽  
Age Related ◽  
Subretinal Fibrosis ◽  
Isolectin B4

Abstract Background Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. Methods Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. Results Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. Conclusions MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Graphical abstract Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch’s membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.

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

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
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.

scholarly journals Potential Sources and Roles of Adaptive Immunity in Age-Related Macular Degeneration: Shall We Rename AMD into Autoimmune Macular Disease?

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Serge Camelo
Keyword(s):  
T Cells ◽  
Macular Degeneration ◽  
Retinal Degeneration ◽  
Adaptive Immunity ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Pathologic Features

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly throughout the industrialized world. Its most prominent pathologic features are lesions involving the retinal pigment epithelium (RPE) the Bruch’s membrane, the degeneration of photoreceptors, and, in the most aggressive cases, choroidal neovascularization. Genetic associations between the risk of developing AMD and polymorphism within components of the complement system, as well as chemokine receptors expressed on microglial cells and macrophages, have linked retinal degeneration and choroidal neovascularization to innate immunity (inflammation). In addition to inflammation, players of the adaptive immunity including cytokines, chemokines, antibodies, and T cells have been detected in animal models of AMD and in patients suffering from this pathology. These observations suggest that adaptive immunity might play a role in different processes associated with AMD such as RPE atrophy, neovascularization, and retinal degeneration. To this date however, the exact roles (if any) of autoantibodies and T cells in AMD remain unknown. In this review we discuss the potential effects of adaptive immune responses in AMD pathogenesis.

Sign in / Sign up

Export Citation Format

Share Document