Effect of Intravitreal Anti-Vascular Endothelial Growth Factor Treatment on the Retinal Gene Expression in Acute Experimental Central Retinal Vein Occlusion

Abstract

Purpose: To determine the effect of intravitreal bevacizumab and anti-vascular endothelial growth factor (VEGF) antibodies on the gene expression in the neural retina in a rat model of central retinal vein occlusion (CRVO). Methods: The CRVO was induced by laser photocoagulation of all retinal veins. The animals were divided into 3 groups (in each, n = 16): group CRVO only without any further treatment, group CRVO with bevacizumab, and group CRVO with anti-VEGF antibodies. The intravitreal injection of bevacizumab or anti-VEGF antibodies was performed 15 min after CRVO induction. The left eyes in all animals served as untreated controls. The expression of factors which influence the development of vascular edema (VEGF-A, pigment epithelium-derived factor, PEDF), of channels implicated in retinal osmohomeostasis (Kir4.1, AQP4, AQP1) and of the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined by using real-time RT-PCR after 1 and 3 days of CRVO. Results: CRVO induced a rapid transient upregulation of Vegfa after 1 day, and a delayed upregulation of Pedf after 3 days of CRVO. The expression levels of Kir4.1, Aqp4 and Aqp1 were strongly decreased, and the levels of Il1β and Il6 were strikingly increased after CRVO. Intravitreal bevacizumab and anti-VEGF antibodies fully prevented the upregulation of Vegfa after 1 day, and the upregulation of Pedf after 3 days of CRVO, and decreased the upregulation of Il1β after 1 day of CRVO. Anti-VEGF treatment had no effect on the expression levels of Kir4.1, Aqp4, Aqp1, and Il6. Conclusions: It is suggested that the inhibitory effect on the upregulation of Vegfa and Il1β contributes to the edema-resolving effect of anti-VEGF treatment.

Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion

“…Serum amyloid A, a major acute phase protein, and the cytokine IL-6, which is derived from activated T lymphocytes and induces expression of VEGF and vascular permeability, have been found to be significantly elevated in the aqueous humour of eyes with CRVO macular oedema compared to control eyes (Feng 2013). In a rat model of CRVO, injection of bevacizumab fully prevented the upregulation of VEGF-A after one day and the upregulation of pigment-epithelium-derived factor after three days, which is known to influence the development of vascular oedema (Drechsler 2012). Bevacizumab also decreased the upregulation of the proinflammatory cytokine interleukin (IL)-1B which otherwise developed one day after a CRVO (Drechsler 2012).…”

“…In a rat model of CRVO, injection of bevacizumab fully prevented the upregulation of VEGF-A after one day and the upregulation of pigment-epithelium-derived factor after three days, which is known to influence the development of vascular oedema (Drechsler 2012). Bevacizumab also decreased the upregulation of the proinflammatory cytokine interleukin (IL)-1B which otherwise developed one day after a CRVO (Drechsler 2012). Furthermore, the concentration of VEGFin human aqueous demonstrates close temporal correlation with the course of neovascularisation and permeability in CRVO, and injecting anti-VEGF antibodies inhibits VEGF-driven neovascularisation both in vitro and in vivo (Adamis 1996; Aiello 1995; Boyd 2002).…”

Animal Models of Retinal Vein Occlusion

“…In most cases, experimental RVO has been induced by traumatizing one or more retinal veins using laser photocoagulation. [67][68][69][70][71][72][73][74][75][80][81][82][83][84][85][86][87][88][89][90][91][92]96,97,101,[104][105][106][107][108][109][110][111][115][116][117][118][125][126][127][129][130][131][132][133][134][135][136][137][138][139]…”

“…69,70,74,80,81,92,97,99,117,186,217 Laser photocoagulation is typically done on the slitlamp using a contact lens. [68][69][70][71][72]74,[81][82][83]86,[88][89][90][91][92]97,99,100,104,108,117,126,132,134,135,137,139,141,186,187,[192][193][194]196 Some studies have combined laser photocoagulation with vitrectomy. 147,[176][177][178] Different types of laser and wavelengths have been used, commonly 514-nm Argon, and their parameters varied depending on the type of laser used, type of animal, and use or not of adjuva...…”

“…147,[176][177][178] Different types of laser and wavelengths have been used, commonly 514-nm Argon, and their parameters varied depending on the type of laser used, type of animal, and use or not of adjuvants (Table 6). Photosensitizers, such as Rose Bengal, 67-70, 73,81,89,96,99-101,104,106,107,109,110,126,127,132,134,135,137,139,141,143, 146,147,217 erythrosin B, 74 sodium fluorescein, 71,83,85,86,88,97,142,175,187,[190][191][192][193][194]218 chloroaluminium sulfonated phthalocyanine, 105 PAD-S31, 186 and mono-L-aspartyl chlorin e6 (NPe6) 82 have been commonly used with the laser photocoagulation to minimize the amount of the laser energy required to produce the RVO. Rose Bengal has been the most commonly used photosensitizer, [67][68][69][70]73,81,89,96,[99][100][101]104,106,107,109,110,126,127,132,…”