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Updated: May 10, 2026
Oxygen-Induced Retinopathy Model for Ischemic Retinal Diseases in Rodents
Published on: September 16, 2020
Ranibizumab efficiently blocks migration but not proliferation induced by growth factor combinations including VEGF
Heidrun L Deissler1, Helmut Deissler, Gerhard K Lang
1Department of Ophthalmology, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany, heidrun.deissler@uniklinik-ulm.de.
Background:
Proliferation and migration of retinal endothelial cells (REC) are associated with the development of proliferative diabetic retinopathy. REC proliferation is stimulated by isoforms of vascular endothelial growth factor-A (i.e., VEGF₁₂₁ and VEGF₁₆₅), basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF-1) of which VEGF₁₆₅ also enhances migration of REC. Effects induced by VEGF-A can be blocked with ranibizumab, a VEGF-binding Fab fragment used in therapy of diabetic macular edema. In this study, we investigated potential angiogenic effects of placental growth factors (PlGF-1, PlGF-2) as other members of the VEGF family and whether the primary action of VEGF₁₆₅ is modulated in the presence of bFGF, IGF-1 and PlGF-1/-2. We also studied how effects of growth factor combinations can be attenuated with ranibizumab.
Methods:
Effects of single growth factors or their combinations on proliferation and migration of immortalized bovine retinal endothelial cells (iBREC) were studied with or without ranibizumab or the inhibitor of VEGF receptors KRN951.
Results:
Proliferation of iBREC was significantly stimulated by 1-100 ng/ml PlGF-1 or PlGF-2, but additive effects were not observed with various combinations of the tested growth factors. Ranibizumab neutralized VEGF's effect on proliferation but was not effective when the other growth factors were used in combination with VEGF. bFGF and IGF-1 but not PlGF-1 or PlGF-2 stimulated iBREC migration as single agents, and they further enhanced VEGF-induced migration. The effects of such growth factor combinations including VEGF on migration were efficiently blocked by targeting only VEGF with ranibizumab. Migration induced by VEGF plus bFGF and IGF-1 was also almost completely inhibited by KRN951 interfering with VEGF receptor signalling.
Conclusions:
Migration but not proliferation of iBREC induced by combinations of bFGF, IGF-1, PlGF-1 or PlGF-2 together with VEGF is efficiently suppressed by ranibizumab. VEGF-mediated signalling through VEGFR2 seems to control REC migration dominantly in the presence of other growth factors.
Insights
Ranibizumab effectively suppresses retinal endothelial cell migration, but not proliferation, when combined with growth factors like VEGF, bFGF, and IGF-1. This suggests VEGF signaling dominantly controls cell migration in proliferative diabetic retinopathy.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Proliferative diabetic retinopathy involves retinal endothelial cell (REC) proliferation and migration.
- Vascular Endothelial Growth Factor-A (VEGF-A) isoforms, basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF-1) stimulate REC proliferation.
- VEGF-A also enhances REC migration, and its effects are targeted by ranibizumab for diabetic macular edema therapy.
Purpose of the Study:
- Investigate angiogenic effects of placental growth factors (PlGF-1, PlGF-2).
- Determine if VEGF₁₆₅ action is modulated by bFGF, IGF-1, and PlGF-1/-2.
- Assess ranibizumab's efficacy in attenuating combined growth factor effects.
Main Methods:
- Studied proliferation and migration of immortalized bovine retinal endothelial cells (iBREC).
- Assessed effects of single growth factors and combinations.
- Utilized ranibizumab (VEGF inhibitor) and KRN951 (VEGF receptor inhibitor).
Main Results:
- PlGF-1 and PlGF-2 stimulated iBREC proliferation, but no additive effects were seen with combinations.
- Ranibizumab blocked VEGF-induced proliferation but not when combined with other growth factors.
- bFGF and IGF-1, but not PlGFs, stimulated iBREC migration and enhanced VEGF-induced migration.
- Ranibizumab efficiently blocked migration induced by VEGF plus other growth factors.
- KRN951 inhibited migration induced by VEGF plus bFGF and IGF-1.
Conclusions:
- Ranibizumab efficiently suppresses migration, but not proliferation, of iBREC induced by combinations of bFGF, IGF-1, PlGF-1/-2 with VEGF.
- VEGF-mediated signaling through VEGFR2 appears to dominantly control REC migration in the presence of other growth factors.
